Systems and Methods for Ex Vivo Organ Care

ABSTRACT

The invention, in various embodiments, provides systems, methods and solutions for perfusing an organ ex vivo.

REFERENCE TO RELATED APPLICATIONS

This application claims, under 35 U.S.C. §121, the benefit of the filingdate of U.S. patent application Ser. No. 11/788,865, filed on Apr. 19,2007, which claims the benefit of the filing date of U.S. patentApplication No. 60/793,472, filed on Apr. 19, 2006, contents of whichare incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The invention generally relates to systems, methods, and devices for exvivo organ care. More particularly, in various embodiments, theinvention relates to caring for an organ ex vivo at physiologic ornear-physiologic conditions.

BACKGROUND OF THE INVENTION

Current organ preservation techniques typically involve hypothermicstorage of the organ in a chemical preservation solution on ice. Thesetechniques utilize a variety of solutions, none of which sufficientlyprotect the organ from damage resulting from ischemia. Such injuries areparticularly undesirable when an organ is intended to be transplantedfrom a donor into a recipient.

Using conventional approaches, such injuries increase as a function ofthe length of time an organ is maintained ex vivo. For example, in thecase of a lung, typically it may be preserved ex vivo for only about 6to about 8 hours before it becomes unusable for transplantation. A hearttypically may be preserved ex vivo for only about 4 to about 6 hoursbefore it becomes unusable for transplantation. These relatively brieftime periods limit the number of recipients who can be reached from agiven donor site, thereby restricting the recipient pool for a harvestedorgan. Even within the time limits, the organs may nevertheless besignificantly damaged. A significant issue is that there may not be anyobservable indication of the damage. Because of this, less-than-optimalorgans may be transplanted, resulting in post-transplant organdysfunction or other injuries. Thus, it would be desirable to developtechniques that can extend the time during which an organ can bepreserved in a healthy state ex vivo. Such techniques would reduce therisk of post-transplant organ failure and enlarge potential donor andrecipient pools.

Effective preservation of an ex vivo organ would also provide numerousother benefits. For instance, prolonged ex vivo preservation wouldpermit more careful monitoring and functional testing of the harvestedorgan. This would in turn allow earlier detection and potential repairof defects in the harvested organ, further reducing the likelihood ofpost-transplant organ failure. The ability to perform simple repairs onthe organ would also allow many organs with minor defects to be saved,whereas current transplantation techniques require them to be discarded.

In addition, more effective matching between the organ and a particularrecipient may be achieved, further reducing the likelihood of eventualorgan rejection. Current transplantation techniques rely mainly onmatching donor and recipient blood types, which by itself is arelatively unreliable indicator of whether or not the organ will berejected by the recipient. A more preferred test for organ compatibilityis a Human Leukocyte Antigen (HLA) matching test, but current coldischemic organ preservation approaches preclude the use of this test,which can often require 12 hours or more to complete.

Prolonged and reliable ex vivo organ care would also provide benefitsoutside the context of organ transplantation. For example, a patient'sbody, as a whole, can typically tolerate much lower levels of chemo-,bio- and radiation therapy than many particular organs. An ex vivo organcare system would permit an organ to be removed from the body andtreated in isolation, reducing the risk of damage to other parts of thebody.

In view of the foregoing, improved systems, methods, and devices forcaring for an organ ex vivo are needed.

SUMMARY OF THE INVENTION

The invention addresses the deficiencies in the state of the art by, invarious embodiments, providing improved systems, methods, solutions anddevices relating to portable ex vivo organ care.

In one aspect of the invention, the invention includes a method forperfusing one or more lungs ex vivo for an extended period of time in a“steady” or “equilibrium” state maintenance mode. The method generallyincludes the step of connecting the lungs within a fluid perfusioncircuit, which includes a pump, a fluid source, and a fluid flowinterface that allows the fluid to flow in and out of the lungs. Themethod also includes the steps of flowing a perfusion fluid into thelungs through a pulmonary artery interface and flowing the perfusionfluid away from the lungs through a pulmonary vein interface,ventilating the lungs through a tracheal interface, which providesperiodic breaths that include alternating inspiration and expiration ofgas in and out of the lungs, similar to inspiration and expiration bylungs in-vivo, and providing a respiratory gas, having a pre-determinedcomposition of gas components, to the lungs for use in metabolism by thelungs. In this method, the perfusion system is brought to a steadystate, wherein the perfusion fluid flowing into the lungs includes gascomponents in a first composition that is substantially constant overtime, and the perfusion fluid flowing away from the lungs includes gascomponents in a second composition that is substantially constant overtime. Because the lungs are separated from the rest of the donor's body,they do not need to supply metabolic requirements for the rest of thebody, such that during perfusion in the systems described herein lessgas exchange is used than lungs in-vivo, and the oxygen and carbondioxide exchange requirement is reduced. The composition of gascomponents in the respiratory gas is thus selected so as to provideadequate oxygen and carbon dioxide to the lungs for metabolism andcontrol of perfusion fluid pH in an amount that approximates physiologiclevels.

In one embodiment, a tracheal oxygen delivery approach is used toimplement the maintenance mode. According to this approach, one or moreexplanted lungs are instrumented within the perfusion circuit and areperfused by a perfusion fluid that is oxygenated to a desired levelprior to initiating the perfusion of the lungs. During perfusion, theoxygenated perfusion fluid flows into the explanted lungs via thepulmonary artery interface and flows away from the lungs via thepulmonary vein interface. In addition, the respiratory gas is deliveredto the lungs by the first gas source through the tracheal interface,such that the explanted lungs are ventilated by a respiratory gas inperiodic breaths through the tracheal interface with alternatinginspiration and expiration periods. In particular, theventilating/respiratory gas delivers a pre-determined composition of gascomponents through the tracheal interface. In certain implementations,the gas flowing through the tracheal interface is a combination havingat least oxygen, carbon dioxide and nitrogen. In certain embodiments,oxygen is about 10% to about 20% and carbon dioxide is about 2% to about8% of the combination. In one embodiment, the ventilating/respiratorygas combination is about 14% oxygen and about 5% carbon dioxide, and thebalance is nitrogen. In this mode, gas leaving the lungs is removed fromthe lungs via the tracheal interface, for example, through an outletvalve located along a conduit extending from the tracheal interface.After perfusing the lungs for a period of time in this mode, steadystate occurs when the first and second gas compositions aresubstantially the same. Upon reaching the steady-state, the oxygen andcarbon dioxide components in the perfusion fluid flowing into the lungsand in the perfusion fluid flowing away from the lungs reach asubstantially constant composition. Moreover, the lungs are perfusedwith the perfusion fluid and ventilated through the tracheal conduit,while the oxygen, carbon dioxide and other gases are maintained in theperfusion fluid at a substantially constant gas component composition,and the gas delivered to the lungs through the tracheal interfacediffers from the second gas composition in an amount sufficient tosupply the lungs' metabolic requirement, and, in certain embodiments,the two gas compositions differ by an amount approximate to support themetabolic requirement.

In another embodiment, an isolated tracheal volume re-breathing approachis used to implement the maintenance mode. In this embodiment, one ormore explanted lungs are first instrumented within the perfusion circuitand are perfused with a perfusion fluid that flows into the lungs viathe pulmonary artery interface and flows away from the lungs via thepulmonary vein interface. A ventilating gas source is provided to thelungs through the tracheal interface, and one or more respiratory gasmixtures, each containing a pre-determined composition of gascomponents, are supplied to the perfusion fluid via a gas exchangedevice (e.g., an oxygenator) in the perfusion circuit. In one exemplaryembodiment, a gas supplied to the gas exchange device is pre-mixed toinclude a desired gas composition for infusion into the perfusion fluid.In another embodiment, gases having different compositions arecontrollably released from the appropriate gas sources to the oxygenator1042 at rates and volumes that allow the desired gas mixture compositionto be obtained.

In certain embodiments, a respiratory gas source may be supplied to thegas exchange device that includes a gas composition of about 3% to about7% carbon dioxide, about 11% to about 14% oxygen, and the balance beingnitrogen. In this mode, the ventilating gas source is provided in anisolated volume that interfaces with other fluids and exchanges withother gases only through the alveoli of the lungs. In certainembodiments, the isolated gas volume is provided by a flexible bag. Incertain embodiments, the isolated gas volume is provided by a hose. Thegas components in the isolated gas volume are able to reach a constantcomposition by exchanging with the gas components in the perfusionfluid. Exhaled carbon dioxide is carried away from the lungs by thecirculating perfusion fluid and substantially removed from the perfusionfluid by mixing with the one or more oxygen-containing gas mixturessupplied through the gas exchange device. In operation, the lungs areventilated during perfusion in this mode by applying a compression forceto the isolated volume. As the isolated volume compresses, itscomponents flow through the tracheal interface and into the lungs, wherethe lungs inflate and the gas components exchange with gas components inthe perfusion fluid through the alveoli in the inflated lungs. As thecompression force is withdrawn from the hose or flexible bag, the lungsexhale. The application and withdrawal of the compression force isrepeated until the gas components flowing into the tracheal interfacereach equilibrium with the components in the perfusion fluid.

Upon reaching a steady state in the isolated tracheal volumere-breathing approach, the oxygen and carbon dioxide components in theperfusion fluid flowing into the lungs includes a substantially constantcomposition and the gas components in the perfusion fluid flowing awayfrom the lungs also include a substantially constant composition. Incertain embodiments, a constant composition of a component is achievedwhen the composition of the component varies over time by an amount lessthan about 3%, less than about 2%, less than about 1% over time in agiven sampling location within the system. Although at a steady state,in the isolated tracheal volume technique, the composition of oxygen andcarbon dioxide in the perfusion fluid flowing into the lungs may differfrom the composition of such components in the perfusion fluid flowingaway from the lungs. In certain embodiments, the compositions of suchcomponents in the in-bound fluid differ from the compositions in theout-bound fluid by amounts substantially equivalent to the quantityresulting from lung metabolism. In certain embodiments, the oxygencomponent is maintained during perfusion at a steady-state partialpressure that is greater in the perfusion fluid flowing into the lungsthan in the perfusion fluid flowing away from the lungs. In certainembodiments, the carbon dioxide component is maintained during perfusionat a steady state partial pressure that is lower in the perfusion fluidflowing into the lungs than in the perfusion fluid flowing out of thelungs.

In certain embodiments of the maintenance mode, the composition of gascomponents in the perfusion fluid is chosen to provide steady-statepartial pressures of the gas components within the circulating fluid ina range between a pre-determined arterial gas composition andpre-determined venous gas composition. In certain embodiments, thepre-determined arterial gas composition is physiologic arterial bloodgas composition, and the pre-determined venous gas composition isphysiologic venous blood gas composition. For example, the compositionof the oxygen component in the perfusion fluid may be at a partialpressure that is greater than a composition of the oxygen component inphysiologic venous blood and less than a composition of the oxygencomponent in physiologic arterial blood. More specifically, this partialpressure of the oxygen component in the perfusion fluid may be betweenabout 60 mmHg to about 100 mmHg, between about 80 mmHg to about 90 mmHg,or between about 83 mmHg to about 85 mmHg. In addition, the compositionof the carbon dioxide component in the perfusion fluid is at a partialpressure that is less than a composition of the carbon dioxide componentin physiologic venous blood and greater than a composition of the carbondioxide component in physiologic arterial blood. More specifically, thispartial pressure of the carbon dioxide component in the perfusion fluidmay be between about 40 mmHg to about 50 mmHg or between about 42 mmHgto about 50 mmHg.

In certain embodiments of the maintenance mode, one or more therapeuticsis delivered to the lungs during perfusion. The one or more therapeuticsmay be selected from antimicrobials, vasodilators, and anti-inflammatorydrugs. The one or more therapeutics may also be selected from isuprel,flolan, prostacycline and nitric oxide donors. In addition, the one ormore therapeutics may be delivered to the lungs through the trachealinterface via a nebulizer, or to the perfusion fluid through amaintenance solution bag, or by injection directly into the perfusionfluid reservoir at the point of use.

In certain embodiments of the maintenance mode, the perfusion fluid ismaintained and provided to the lungs at a near physiologic temperature.According to one implementation, the perfusion fluid employs a bloodproduct-based perfusion fluid to more accurately mimic normalphysiologic conditions. In alternative embodiments, a synthetic bloodsubstitute solution is used, while in other embodiments, the solutionmay contain a blood product in combination with a blood substituteproduct. The perfusion fluid may include a blood product, such as wholeblood, and it may be partially or completely depleted of leukocytesand/or platelets.

In certain embodiments, one or more tests can be performed on the lungswhile they are maintained in the perfusion circuit for ex vivo care. Forexample, levels of an arterial-venous (AV) oxygen gradient between theperfusion fluid flowing into the lungs and flowing away from the lungscan be measured. Levels of oxygen saturation of blood hemoglobin in theperfusion fluid flowing into the lungs and flowing away from the lungscan also be measured, as can pulmonary vascular resistance ventilationrate, tidal volume, peak respiratory pressure and positiveend-expiratory pressure (PEEP).

According to another aspect of the invention, the invention includes alung care system for perfusing one or more lungs ex vivo. The exemplarysystem includes a portable multiple use module and a single usedisposable structure that is sized and shaped for interlocking with themultiple use module. The single use module also includes a lung chamberassembly mounted to the disposable structure. The exemplary system alsoincludes a pump adapted to deliver a perfusion fluid to the lung chamberassembly. The lung chamber assembly includes a pulmonary arteryinterface for allowing a flow of the perfusion fluid into the lungs, atracheal interface for allowing ventilation of the lungs, and apulmonary vein interface for allowing the perfusion fluid to flow awayfrom the lungs. In addition, the single use module may include arespiratory gas source having a predetermined gas component composition.In certain embodiments, the respiratory gas source is included in themultiple-use module.

In certain embodiments, the pulmonary vein interface of the lung caresystem includes a portion of the donor's left atrium, which is severedfrom the donor upon explanting the lungs. A portion of the left atrium,known as the left atrial cuff, is left to hang freely from the lungs andis exposed to the lung chamber assembly for allowing the perfusion fluidto flow from the lungs to the lung chamber assembly. In certainembodiments, the pulmonary vein interface includes a cannulation to theleft atrial cuff. In one example of cannulation to the left atrial cuff,a semi-sealable connection between the left atrial cuff and a cannula isformed that directs the perfusion fluid to a reservoir. Thesemi-sealable connection may be formed by a connector device that matesthe cannula with the left atrial cuff, and the connection may bereleasable. In one instance, the connector device includes a firstsurface for engaging the left atrial cuff and a second surface forengaging the cannula. In one instance, the first surface of theconnector device includes a plurality of perforations for engaging aplurality portions of the left atrial cuff. The left atrial cuff mayalso extend vertically above the lungs and fit semi-sealably within avertically extending cannula, wherein the cannula has a cross-sectionwith a diameter that is larger than a diameter of the left atrial cuff.The cannula can be loosely fitted around the left atrial cuff. In otherpractices, cannulation to the left atrial cuff can be formed by sealinga tip portion of the cannula substantially within a pocket formed by theleft atrial cuff. In yet another embodiment, the pulmonary veininterface includes the left atrial cuff disposed in a cup-shapedinterface inside of the lung camber assembly for allowing the perfusionfluid to flow from the lungs and away from the lung chamber assembly viaan outlet conduit coupled to the cup-shaped interface. The cup-shapedinterface may additionally include multiple openings at respectiveheights along a sidewall of the interface, and the openings are in fluidcommunication with a selector valve. The selector value is used tocontrollably draw the perfusion fluid in the cup-shaped interface awayfrom the lung chamber assembly through a selected one of the multipleopenings and through the outlet conduit. Hence, the perfusion fluid isable to fill the cup-shaped interface to a height where the selectopening is located in order to create a desired level of back pressureon the pulmonary veins.

In certain embodiments of the lung chamber assembly, a housing ismounted inside of the lung chamber assembly for supporting the lungs.The housing substantially prevents the lungs from contacting at leastone wall of the lung chamber assembly. The housing may be stiff orflexible, and is configured to distribute the weight of the lungs asevenly as possible about the surface of the lungs. In this manner it isbelieved that pressure upon the alveoli of the lungs can be reduced. Inone practice, the housing includes a flexible membrane, such as a cloth,a netting or other fabric, that suspends the lungs within the lungchamber assembly. In another practice, the housing has a shape of astiff or flexible ribcage having, optionally, a diaphragm structureand/or padding.

The system may also include a heater for maintaining the perfusion fluidprovided to the lung chamber assembly at a near physiologic temperature.The system may additionally include a gas exchange device in fluidcommunication with at least one gas supply and the perfusion fluid, thegas exchange device being adapted to controllably modulate thecomposition of a gas component in the perfusion fluid. In certainembodiments, the gas exchange device (e.g., an oxygenator) includes agas select switch for selecting from a plurality of gas supplies tomodulate the composition of a gas component in the perfusion fluid. Thesystem may further include a respiration device for providing a gassupply through the tracheal interface. To operate the system in theisolated tracheal mode, a volume compartment may be cannulated to atracheal conduit of the lungs and adapted to ventilate the lungs duringperfusion.

In another aspect of the invention, the invention includes a method foroperating a perfusion circuit in an evaluation mode. One or more lungsmay be evaluated for transplant suitability during the evaluation mode.The method includes positioning the lungs in an ex vivo perfusioncircuit, flowing a perfusion fluid into the lungs through a pulmonaryartery interface, and flowing the perfusion fluid away from the lungsthrough a pulmonary vein interface, the perfusion fluid being at aphysiologic temperature. In addition, the method includes providing gascontaining oxygen to the lungs through a tracheal interface. The oxygenlevel in the gas can be adjusted to allow for evaluation at variousoxygen composition levels. The gas may comprise about 100% oxygen, lessthan 100% oxygen, less than about 75% oxygen, less than about 50%oxygen, less than about 25% oxygen, or no oxygen. In certainembodiments, this gas may be the same composition as ambient air.

The evaluation mode is useful, for example, for performing tests toevaluate the gas-transfer capacity of the lungs by determining theoxygen or carbon dioxide saturation or partial pressure of oxygen in theperfusion fluid both before and after it flows through the lungs. Toperform this test in the evaluation mode, a low-oxygen content gassource is used to adjust the gas content of the perfusion fluid suchthat the fluid resembles that of physiologic venous blood. The blood gascomposition of the perfusion fluid is then monitored by taking samplemeasurements of oxygen saturation or partial pressure of gas componentsin the perfusion fluid flowing into the lungs via the pulmonary arteryinterface and flowing away from the lungs via the pulmonary veininterface. The resulting pulmonary artery and pulmonary vein oxygensaturation or partial pressure measurements, collected over a period oftime after ventilation begins, are then compared with each other toidentify a maximum difference that is representative of the gas-transfercapacity of the lungs.

Other evaluations can be performed on the instrumented lungs. Theseevaluations include measuring a fractional inspired oxygenconcentration, measuring an arterial-venous (AV) oxygen gradient betweenthe perfusion fluid flowing into the lungs and the perfusion fluidflowing away from the lungs, measuring an alveolar arterial (AA) oxygengradient, measuring a tidal volume, measuring oxygen saturation of bloodhemoglobin or partial pressure of oxygen in the perfusion fluid flowinginto and away from the lungs, and measuring the PEEP.

In certain embodiments of the evaluation mode, a suction force isapplied through the tracheal interface to clear lungs alveoli of debris.The lung alveoli debris may also be cleared by causing the lungs toinhale breaths that are of variable volume. For example, in sighbreathing, the breaths include a first breath having a volume that islarger than the volume of at least two next breaths.

In another aspect of the invention, the invention includes compositionsand solutions for infusion into a perfusion fluid that is used toperfuse the lungs prior to transplantation. The solutions include asubstantially cell-free composition, where the compositions comprise oneor more carbohydrates that include dextran, and a plurality of aminoacids that do not include asparagine, glutamine, or cysteine.

According to various aspects, the systems and/or devices of theinvention include, and/or the methods of the invention employ, one ormore of an lung chamber assembly sized and configured for containing oneor more lungs during ex vivo care; a reservoir for containing andoptionally, defoaming and/or filtering a volume of perfusion fluid; aperfusion fluid pump for pumping/circulating perfusion fluid to and fromthe harvested lungs; a heater assembly for maintaining the temperatureof the perfusion fluid at or near to physiologic temperatures; a gasexchange device for exchanging gases with the perfusion fluid in thesystem; a nutritional subsystem for replenishing nutrients in theperfusion fluid as they are metabolized by the lungs and for providingpreservatives to the perfusion fluid to reduce, for example, ischemia,edema and/or other reperfusion related injuries to the lungs; a sensorsubsystem for monitoring, for example, temperature, pressure, flow rateand/or oxygenation of the perfusion fluid, and/or the various componentsemployed to maintain suitable flow conditions to and from the lungs; anoperator interface for assisting an operator in monitoring systemoperation and/or the condition of the lungs, and/or for enabling theoperator to set various operating parameters; a power subsystem forproviding fault tolerant power to the organ care system; and a controlsubsystem for controlling operation of the organ care system.

Operationally, in one practice, the lungs are harvested from a donor andis instrumented to the lung chamber assembly by processes describedabove. The perfusion fluid pump pumps perfusion fluid from a reservoirto the heater assembly. The heater assembly heats the perfusion fluid toor near a normal physiologic temperature. According to one embodiment,the heater assembly heats the perfusion fluid to between about 30° C.and about 37° C., or in between about 34° C. and 37° C. From the heaterassembly, the perfusion fluid flows to a first interface on the lungchamber assembly. Also referred to as a pulmonary artery interface, thefirst interface is cannulated to vascular tissue of the pulmonary arteryvia a conduit located within the lung chamber assembly. The perfusionfluid then flows out of the lungs through the pulmonary vein via asecond interface on the lung chamber assembly. The second interface,also referred to as a pulmonary vein interface, connects to theremainder of the perfusion circuit as described above. Optionally, thepulmonary vein is allowed to drain directly into the lung chamberassembly without cannulation. From the pulmonary vein interface, theperfusion fluid flows back to a fluid reservoir, where it may be infusedwith nutrients prior to recirculation through the perfusion circuit.

When applicable (e.g., during the isolated tracheal volume mode), a gasexchange device is positioned within the perfusion circuit between thefluid reservoir and the lung chamber assembly. The gas exchange devicereceives a gas from an external or onboard gas source and applies gas(e.g., oxygen, a mixture of oxygen and carbon dioxide, or a mixture ofoxygen, carbon dioxide and nitrogen) to the perfusion fluid prior toflowing the fluid into the lungs. Alternatively, oxygen and other bloodgas levels may be determined by drawing fluid samples from the perfusionfluid and analyzing the samples in a commercially available blood gasanalyzer or using partial pressure sensors onboard the system. Thesystem may include one or more oxygen saturation sensors to measure theoxygen saturation level of the perfusion fluid to ensure that theperfusion fluid is maintained at physiologic or other user-definedoxygen levels. In the embodiments where the perfusion fluid isblood-product based, it contains red blood cells (i.e., oxygen carryingcells). Optionally, the oxygen sensors also provide a hematocritmeasurement of the concentration of red blood cells in the perfusionfluid.

The nutritional subsystem infuses the perfusion fluid with a supply ofmaintenance solutions as the perfusion fluid flows through the system,and in some embodiments, while it is in the reservoir. According to onefeature, the maintenance solutions include nutrients, such as glucose.According to another feature, the maintenance solutions include a supplyof therapeutics, vasodilators, endothelial stabilizers, and/orpreservatives for reducing edema and providing endothelial support tothe lungs.

According to another practice, the perfusion fluid includes bloodremoved from the donor through a process of exsanguination duringharvesting of the lungs. Initially, the blood from the donor is loadedinto the reservoir and the cannulation locations in the lung chamberassembly are bypassed with a bypass conduit to enable normal mode flowof perfusion fluid through the system without a lung being present.Prior to cannulating the harvested lungs, the system may be primed bycirculating the exsanguinated donor blood through the system to heatand/or filter it, and, if desired, oxygenate it.

In one embodiment, the portable multiple use module includes a portablehousing constructed on a portable chassis, and the single use disposablemodule includes a disposable structure, such as a housing or a frame. Toreduce weight, in one configuration, the disposable structure along withvarious components of the single use module are formed from moldedplastic such as polycarbonate, and the multiple use module chassis isformed from molded materials such as polycarbonate or carbon fibercomposites. According to one feature, the unloaded single use disposablestructure weighs less than about 12 pounds and the loaded single usemodule weighs less than about 18 pounds. According to another feature,the multiple use housing and chassis unloaded with components weighsless than about 50 pounds, and when loaded with a multiple use module,batteries, gas, maintenance solutions, perfusion fluid and an organ,weighs about 85 pounds or less. According to another advantage, thesystem of the invention including both single and multiple use modules,exclusive of any perfusion, nutrient, preservative or other fluids,batteries and gas supply, weighs less than about 65 pounds.

The single use disposable structure (e.g., frame or housing) is sizedand shaped for interlocking with the portable chassis of the multipleuse module for electrical, mechanical, gas and fluid interoperation withthe multiple use module. According to one feature, the multiple andsingle use modules communicate with each other via an optical interface,which comes into optical alignment automatically upon the single usedisposable module being installed into the portable multiple use module.According to another feature, the portable multiple use module providespower to the single use disposable module via spring loaded connections,which also automatically connect upon the single use disposable modulebeing installed into the portable multiple use module. According to onefeature, the optical interface and spring loaded connections ensure thatpower and data connection between the single and multiple modules is notlost due to jostling, for example, during transport over rough terrain.

In various embodiments, the lung chamber assembly mounts to thedisposable structure.

In one configuration, the various sensors associated with the heaterassembly, the gas exchange device and/or the perfusion fluid pump areincluded on the disposable single use module. However, this need not bethe case, for example, with regard to non-perfusion fluid contactingsensors. According to one embodiment, the single use disposable moduleemploys an oxygen sensor including in-line cuvette through which theperfusion fluid passes, an optical source for directing light at theperfusion fluid passing through the cuvette, and an optical sensor formeasuring an optical quality of the perfusion fluid passing through thecuvette. Preferably, the in-line cuvette seamlessly or substantiallyseamlessly attaches to a perfusion fluid flow conduit to reduceturbulence in the perfusion fluid and provide one or more accuratemeasurements. The seamless or substantially seamless configuration alsoreduces damage to any blood based components of the perfusion fluid.

According to a further configuration, the disposable single-use moduleincludes the above-mentioned plurality of inline compliance chamberslocated, for example, at an outlet of the perfusion fluid pump, anoutlet of the gas exchange device or an outlet of the heater assembly.In a further embodiment, the disposable single-use module includes aplurality of ports for sampling fluids from the lung chamber assembly.

In a further aspect, the invention is directed to a method oftransporting one or more lungs ex vivo, including the steps of placingthe lungs for transplantation in a protective chamber of a portableorgan care system, pumping a perfusion fluid into the lungs via apulmonary artery of the lungs, providing a flow of the perfusion fluidaway from the lungs via a pulmonary vein of the lungs, and transportingthe lungs in the portable organ care system from a donor site to arecipient site while pumping the perfusion fluid into an artery of thelungs.

These and other features and advantages of the invention are describedin further detail below with regard to illustrative embodiments of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures depict illustrative embodiments of the inventionin which like reference numerals refer to like elements. These depictedembodiments may not be drawn to scale and are to be understood asillustrative of the invention and not as limiting, the scope of theinvention instead being defined by the appended claims.

FIG. 1 is a schematic diagram of a portable organ care system accordingto an illustrative embodiment of the invention.

FIG. 2 is a diagram depicting a harvested heart.

FIG. 3 is a conceptual diagram depicting the harvested heart of FIG. 2interconnected with the organ care system of FIG. 1 in a normal flowmode configuration according to an illustrative embodiment of theinvention.

FIG. 4 is a conceptual diagram depicting the harvested heart of FIG. 2interconnected with the organ care system of FIG. 1 in a retrograde flowmode configuration according to an illustrative embodiment of theinvention.

FIGS. 5A-5F show various views of an organ chamber assembly of the typeemployed in the organ care system of FIG. 1 according to an illustrativeembodiment of the invention.

FIGS. 6A-6F show various views of a perfusion heater assembly of thetype employed in the organ care system of FIG. 1 according to anillustrative embodiment of the invention.

FIG. 7 shows a more detailed view of an exemplary resistive heaterelement of the type employed in the heater assembly of FIGS. 6A-6F.

FIGS. 8A-8C show various views of a perfusion fluid pump interfaceassembly according to an illustrative embodiment of the invention.

FIG. 9 shows a perspective view of a pump driver side of a perfusionfluid pump assembly of the type depicted in FIG. 1, along with a bracketfor mounting with the perfusion pump interface assembly.

FIG. 10 shows a side view of the perfusion fluid pump interface assemblyof FIGS. 8A-8C mated with the pump driver side of the perfusion fluidpump assembly of FIG. 9.

FIG. 11 depicts a block diagram of an illustrative control scheme forcontrolling operation of the organ care system of FIG. 1.

FIG. 12 is a block diagram of an exemplary data acquisition subsystem ofthe type that may be employed with an the illustrative organ care systemof FIG. 1.

FIG. 13 is a block diagram of an exemplary heating control subsystem ofthe type that may be employed for maintaining perfusion fluidtemperature in the illustrative organ care system of FIG. 1.

FIG. 14 is a block diagram of an exemplary power management subsystem ofthe type that may be employed in the illustrative organ care system ofFIG. 1.

FIG. 15 is a block diagram of an exemplary pumping control subsystem ofthe type that may be employed for controlling operation of a perfusionfluid pump assembly in the illustrative organ care system of FIG. 1.

FIG. 16 is a graph depicting an r-wave with which the pumping controlsubsystem of FIG. 15 synchronizes according to an illustrativeembodiment of the invention.

FIG. 17A-17J depict exemplary display screens of the type that may beemployed with an operator interface according to an illustrativeembodiment of the invention.

FIGS. 18A and 18B show an exemplary implementation of the system of FIG.1 according to an illustrative embodiment of the invention.

FIGS. 19A-19C show various views of the system of FIGS. 18A and 18B withits top off and front panel open according to an illustrative embodimentof the invention.

FIG. 20A is a front perspective view of the system of FIGS. 18A and 18Bwith the top removed, the front panel open and the single use disposablemodule removed according to an illustrative embodiment of the invention.

FIG. 20B is a side view of a slot formed in a basin of the multiple usemodule of FIG. 20A for engaging with a corresponding projection in thesingle use disposable module.

FIG. 21A shows a mounting bracket for receiving and locking into placethe single use disposable module within the multiple use module of FIG.20A.

FIGS. 21B and 21C show installation of the single use disposable moduleinto the multiple use module using the mounting bracket of FIG. 21Aaccording to an illustrative embodiment of the invention.

FIGS. 22A-22C show exemplary mechanisms for automatically makingelectro-optical interconnections between the single use disposablemodule and the multiple use module during the installation of FIGS. 21Band 21C.

FIGS. 23A-23C show various views of the system of FIGS. 18A and 18B withall of the external walls removed according to an illustrativeembodiment of the invention.

FIG. 23D is a conceptual diagram showing interconnections between thecircuit boards of FIGS. 23A-23C according to an illustrative embodimentof the invention.

FIGS. 24A-24E show various top perspective views of a single usedisposable module according to an illustrative embodiment of theinvention.

FIGS. 25A-25C show various bottom perspective views of the illustrativesingle use disposable module of FIGS. 24A-24D.

FIGS. 26A and 26B depict the operation of a flow mode selector valveaccording to an illustrative embodiment of the invention.

FIGS. 27A and 27B show various top views of the single use disposablemodule of FIGS. 19A-19C with the top off of illustrative organ chamber.

FIGS. 28A-28C show various views of an exemplary hematocrit and oxygensaturation sensor of the type employed in the illustrative single usedisposable module of FIGS. 19A-19C.

FIG. 29A is a flow diagram depicting a donor-side process for removingan organ from a donor and placing it into the organ care system of FIG.1 according to an illustrative embodiment of the invention.

FIG. 29B is a diagram depicting a harvested heart with suture andcannulation sites according to an illustrative embodiment of theinvention.

FIG. 30 is a flow diagram depicting a recipient-side process forremoving an organ from the organ care system of FIG. 1 and transplantingit into a recipient according to an illustrative embodiment of theinvention.

FIG. 31 depicts a chart demonstrating electrolyte stability for an organunder going perfusion in forward mode according to an embodiment of theinvention.

FIG. 32 depicts a chart demonstrating electrolyte stability for an organunder going perfusion in retrograde mode according to another anembodiment of the invention.

FIG. 33 depicts a chart demonstrating the arterial blood gas profile foran organ under going perfusion according to an embodiment of theinvention.

FIG. 34 is a schematic diagram of a portable lung care system with adisposable module configured according to an illustrative embodiment ofthe invention.

FIG. 35A is a diagram depicting a pair of harvested lungs.

FIG. 35B is a diagram depicting a single harvested lung.

FIG. 36 is a diagram depicting a portion of a body's pulmonary circuitfrom which at least one lung may be harvested.

FIG. 37 is a flow diagram depicting an exemplary process forimplementing a maintenance mode of operation within the lung care systemof FIG. 34.

FIG. 38 is a flow diagram depicting another exemplary process forimplementing a maintenance mode of operation within the lung care systemof FIG. 34.

FIG. 39 shows exemplary measurement data collected during a maintenancemode operation of the lung care system.

FIG. 40 is a flow diagram depicting an exemplary process forimplementing an evaluation mode of operation within the lung care systemof FIG. 34.

FIG. 41 shows an embodiment of the disposable module configured topreserve the harvested lungs of FIG. 35A.

FIG. 42 shows another embodiment of the disposable module configured topreserve the harvested lungs of FIG. 35A.

FIG. 43 shows yet another embodiment of the disposable module configuredto preserve the harvested lungs of FIG. 35A.

FIG. 44 depicts a top view and a profile view of an exemplary lungchamber assembly employed in the illustrative single use disposablemodule of FIGS. 41-43.

FIG. 45 depicts a top view and a profile view of another exemplary lungchamber assembly employed in the illustrative single use disposablemodule of FIGS. 41-43.

FIG. 46 depicts a top view and a profile view of another exemplary lungchamber assembly employed in the illustrative single use disposablemodule of FIGS. 41-43.

FIG. 47 depicts a top view and a profile view of yet another exemplarylung chamber assembly employed in the illustrative single use disposablemodule of FIGS. 41-43.

FIG. 48A and FIG. 48B show various views of an exemplary connectordevice used for cannulating the pair of harvested lungs of FIG. 35A.

FIG. 49A and FIG. 49B show various views of another exemplary connectordevice used for cannulating the pair of harvested lungs of FIG. 35A.

FIG. 50A and FIG. 50B show various views of yet another exemplaryconnector device used for cannulating the pair of harvested lungs ofFIG. 35A.

FIG. 51A depicts an illustrative arrangement for cannulating the pair ofharvested lungs of FIG. 35A.

FIG. 51B depicts an exemplary cup-shaped interface according to anembodiment of the invention.

FIG. 52 depicts an illustrative screen for real-time displaying andplotting of data collected from the lung care system of FIG. 34.

FIG. 53 is a flow diagram depicting a donor-side process for removinglungs from a donor and placing them into the lung care system of FIG. 34according to an illustrative embodiment of the invention.

FIG. 54 is a flow diagram depicting a recipient-side process forremoving lungs from the lung care system of FIG. 34 and transplantingthem into a recipient according to an illustrative embodiment of theinvention.

DETAILED DESCRIPTION

As described above in summary, the invention generally provides improvedapproaches to ex vivo organ care. More particularly, in variousembodiments, the invention is directed to improved systems, methods anddevices relating to maintaining an organ in an ex vivo portableenvironment. According to one improvement, the organ maintenance systemof the invention maintains a heart beating at or near normal physiologicconditions. To this end, the system circulates an oxygenated, nutrientenriched perfusion fluid to the heart at near physiologic temperature,pressure and flow rate. In other embodiments the system maintains otherorgans, such as one or more lungs, at or near normal physiologicconditions. According to one implementation, the system employs aperfusion fluid solution that more accurately mimics normal physiologicconditions. In one embodiment, the perfusion fluid is blood-productbased. In alternative embodiments, the solution is synthetic bloodsubstitute based. In other embodiments the solution may contain a bloodproduct in combination with a blood substitute product. The bloodproduct may be derived from donor blood or blood from a blood bank.

According to various illustrative embodiments, the improvements of theinvention enable an organ to be maintained ex vivo for extended periodsof time, for example, exceeding 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20,22, 24 or more hours. Such extended ex vivo maintenance times expand thepool of potential recipients for donor organs, making geographicdistance between donors and recipients less important. Extended ex vivomaintenance times of the invention also provide the time needed forbetter genetic and HLA matching between donor organs and organrecipients, increasing the likelihood of a favorable outcome. Theability to maintain the organ in a near physiologic functioningcondition also enables a clinician to evaluate the organ's function exvivo, further increasing the likelihood of transplantation success. Insome instances, the extended maintenance time enables medical operatorsto perform repairs on donor organs with minor defects. According toanother advantage, the increased ex vivo organ maintenance times of theinvention enable an organ to be removed from a patient, treated inisolation ex vivo, and then put back into the body of a patient. Suchtreatment may include, without limitation, pharmaceutical treatments,gas therapies, surgical treatments, chemo-, bio-, gene and/or radiationtherapies.

The illustrative systems, methods and devices of the invention aredescribed below in the following order. First, the components of anillustrative organ care system 100 for use with a heart are described.Second, illustrative operation of the system 100 is discussed. Third, asubset of the components of the system 100 are described in furtherdetail. Fourth, illustrative control systems and methods for the system100 are discussed. Fifth, an illustrative user interface is described.Sixth, mechanical features of the system 100 are discussed in furtherdetail with regard to an exemplary implementation. Seventh, exemplarymethods for employing the system 100 during an organ harvest, transport,and transplantation procedure are described. Eighth, illustrativeimplementations of a system 1000 adapting the system 100 for preservinglungs are described, and ninth illustrative perfusion, nutritional andpreservative solutions suitable for use with the system 1000 arepresented.

Turning to the illustrative embodiments, FIG. 1 depicts a schematicdiagram of a portable organ care system 100 according to an illustrativeembodiment of the invention. FIG. 2 shows a conceptual drawing of aheart 102, which may be preserved/maintained ex vivo by the organ caresystem 100 of the invention. Referring to FIGS. 1 and 2, theillustrative system 100 includes an organ chamber assembly 104 forcontaining the heart 102 during ex vivo maintenance, a reservoir 160 forholding, defoaming and filtering the perfusion fluid 108, portal 774 forloading perfusion fluid 108 into the reservoir 160 and a portal 762 forapplying therapeutics to the fluid 108 contained in the reservoir 160, aperfusion fluid pump 106 for pumping/circulating perfusion fluid 108 toand from the harvested heart 102; a heater assembly 110 for maintainingthe temperature of the perfusion fluid 108 at or near physiologicaltemperatures; a flow mode selector valve 112 for switching betweennormal and retrograde aortic flow modes (also referred to as “normalflow mode” and “retrograde flow mode,” respectively); an oxygenator 114for re-oxygenating the perfusion fluid 108 subsequent to it beingexpelled by the heart 102; a nutritional subsystem 115 for replenishingnutrients 116 in the perfusion fluid 108 as they are metabolized by theheart 102 and for providing additional preservatives 118 to theperfusion fluid to reduce, for example, ischemia and/or otherre-perfusion related injuries to the heart 102. The illustrative system100 also includes a plurality of sensors, including without limitation:temperature sensors 120, 122 and 124; pressure sensors 126, 128, 130 and132; perfusion flow rate sensors 134, 136 and 138; a perfusion fluidoxygenation sensor 140; and sensor electrodes 142 and 144, anddefibrillation source 143. The system 100 further includes: variouscomponents employed for maintaining suitable flow conditions to and fromthe heart 102; an operator interface 146 for assisting an operator inmonitoring operation of the system 100, and the condition of the heart102, and for enabling the operator to select various operatingparameters; a power subsystem 148 for providing fault tolerant power tothe system 100; and a controller 150 for controlling operation of theorgan care system 100.

Referring also to FIGS. 3 and 4, according to the illustrativeembodiment, the system 100 can maintain the heart 102 in two modes ofoperation—a normal flow mode, shown in FIG. 3, and a retrograde flowmode shown in FIG. 4. Generally, in the normal flow mode of FIG. 3, thesystem 100 circulates the perfusion fluid 108 to the heart 102 in thesame manner as blood would circulate in the human body. Moreparticularly, referring to FIGS. 1-3, the perfusion fluid enters theleft atrium 152 of the heart 102 via the pulmonary vein 168. Theperfusion fluid 108 is flowed away from the right ventricle 154 via thepulmonary artery 164 and away from the left 156 ventricle via the aorta158. In normal flow mode, the system 100 pumps the perfusion fluid tothe heart 102 at a near physiological rate of between about 1 liter/minand about 5 liters/minute. This mode is useful, for example, forperforming functional testing to verify that the heart 102 is defectfree, both prior and subsequent to transportation to a donor location.

Alternatively, in retrograde flow mode, shown in FIG. 4, the system 100flows the perfusion fluid 108 into the heart 102 via the aorta 158,through the coronary sinus 155 and other coronary vasculature of theheart, and out of the right ventricle 154 of the heart 102 via thepulmonary artery 164. As discussed in further detail below with regardto FIGS. 24A and 24B, the system 100 also provides a trickle flow 769 tothe left atrium 152 through trickle valve 768. The trickle flow isprovided in an amount sufficient to moisten the left atrium 152 and leftventricle 156. In certain applications the trickle flow is less thanabout 5 ml/min, less than about 1 ml/min, or less than about 0.1 ml/min.In this mode of operation, the system 100 reduces the flow rate of theperfusion fluid 108 to between about 300 milliliters/minute and about 1liter/minute. The inventors have found that the retrograde flow path ofFIG. 4, along with the reduced flow rate, reduces damage to the heart102 during extended periods of ex vivo maintenance. Thus, according toone feature of the invention, the heart 102 is transported to a donorsite in retrograde flow mode.

Having briefly described the normal and retrograde flow modes, thesystem 100 will next be described in further detail operationally.Referring once again to FIGS. 1-4, in one practice, the heart 102 isharvested from a donor and cannulated into the organ chamber assembly104. The perfusion fluid 108 is prepared for use within system 100 bybeing loaded into the reservoir 160 via portal 774 and, optionally,being treated with therapeutics via portal 762. The pump 106 pumps theloaded perfusion fluid 108 from a reservoir 160 to the heater assembly110. The heater assembly 110 heats the perfusion fluid 108 to or near anormal physiological temperature. According to one embodiment, theheater assembly 110 heats the perfusion fluid to between about 32° C.and about 37° C. The heater assembly 110 has an internal flow channelwith a cross-sectional flow area that is approximately equal to theinside cross-sectional area of fluid conduits that carry the perfusionfluid 108 into and/or away from the heater assembly 110, so as tominimize disturbance of fluid flow. From the heater assembly 110, theperfusion fluid 108 flows to the flow mode selector valve 112.

Initially, the flow mode selector valve 112 is positioned in retrogrademode to direct the perfusion fluid 108 from the heater assembly 110 intothe organ chamber assembly 104 via a first interface 162. Also referredto as an aorta interface or left ventricle interface, the interface 162includes cannulation to vascular tissue of the left ventricle via anaperture 228 b located on the organ chamber assembly 104 (as shown inFIGS. 5A-5B). As the heart 102 warms, it begins to beat which causes theheart 102 to pump the perfusion fluid 108 through the coronaryvasculature 155 and out of the heart 102 through the right ventricle 154via a second interface 166. The second interface 166, also referred toas a pulmonary artery interface or a right ventricle interface, includescannulation to vascular tissue of the right ventricle via an aperture228 c located on the organ chamber assembly 104 (as shown in FIGS.5A-5B). As mentioned above, in retrograde flow mode, fluid is notactively pumped into or out of the left side of the heart, except for arelatively small trickle 769 of perfusion fluid, which is delivered tomoisten the left atrium 152 and left ventricle 156, as described belowin reference to FIGS. 24A-24E.

In response to the flow mode selector valve 112 being placed in thenormal mode position, it directs the perfusion fluid 108 into the leftatrium 152 of the heart 102 via a third interface 170. The thirdinterface 170, also referred to as a pulmonary vein interface or leftatrium interface, includes cannulation to vascular tissue of the leftatrium 152 via an aperture 228 a located on the organ chamber assembly104 (as shown in FIGS. 5A-5B). The heart 102 then expels the perfusionfluid 108 through the left ventricle 156 via the aorta interface 162 andthrough the right ventricle 154 via the pulmonary artery interface 166.

Each of the interfaces 162, 166 and 170 may be cannulated to the heart102 by pulling vascular tissue (e.g., an aorta stub) over the end of theinterface, then tying or otherwise securing the tissue to the interface.The vascular tissue is preferably a short segment of a blood vessel(e.g., an aorta stub 158) that remains connected to the heart 102 afterthe heart 102 is severed and explanted from the donor. For example, theaorta interface 162 is cannulated to a small segment of the severedaorta 158 which has been formed by severing the aorta 158 in a locationdown-stream from the coronary sinus 155. In certain applications, theshort vessel segments may be about 5 to about 10 inches in length orlonger. The segments may also be shorter than about 5 inches. Thesegments may be about 2 to about 4 inches in length, or about 1 to about2 inches in length; in other applications the segments may be less thanabout ½ inch, or less than about 1/4 inch.

Alternatively, the cannulation may occur by affixing the interfacedirectly to the applicable atrium or ventricle, as may be preferred inapplications where the heart 102 is prepared for explanation by severingan entire blood vessel without leaving any stub portion of the vesselconnected to the heart 102. For example, a left atrium 152 cannulationcan be formed by inserting the interface 170 directly into the leftatrium 152 and clamping the interface 170 in place, without the need totie to any pulmonary vein 168 tissue.

With continued reference to FIG. 1, in both flow modes the perfusionfluid 108 flows from the pulmonary artery interface 166 into theoxygenator 114. The oxygenator 114 receives gas from an external oronboard source 172 through a gas regulator 174 and a gas flow chamber176, which can be a pulse-width modulated solenoid valve that controlsgas flow, or any other gas control device that allows for precisecontrol of gas flow rate. A gas pressure gauge 178 provides a visualindication of how full the gas supply 172 is. The transducer 132provides similar information to the controller 150. The controller 150can regulate automatically the gas flow into the oxygenator 114 independence, for example, on the perfusion fluid oxygen content measuredat the sensor 140. According to various illustrative embodiments, theoxygenator 114 is a standard membrane oxygenator, such as the Liliput 2manufactured by Dideco, a division of Sorin Biomedical, or the MINIMAXPLUS™ manufactured by Medtronic, Inc. In the illustrative embodiment,the gas includes an oxygen and carbon dioxide mixture. An exemplarycomposition of such a mixture contains about 85% O₂, about 1% CO₂, withthe balance being N₂. Subsequent to re-oxygenation, the oxygenator 114returns the perfusion fluid 108 to the reservoir 160. According to theillustrative embodiment, the sensor 140 measures the amount of lightabsorbed or reflected by the perfusion fluid 108 when applied at amulti-wavelength to provide an optical-based measurement of oxygensaturation. Since the perfusion fluid 108 is blood product based incertain embodiments, it may contain red blood cells (i.e., oxygencarrying cells). Accordingly, the sensor 140 also provides a signal 145indicative of a hematocrit measurement of the perfusion fluid 108. Inalternative embodiments the solution 108 is formed of a synthetic bloodsubstitute, while in other embodiments, the solution 108 may contain ablood product in combination with a blood substitute product.

Also, in both flow modes, the nutritional subsystem 115, including asupply of maintenance solutions 116/118 and an infusion pump 182,infuses the perfusion fluid 108 with nutrients 116, such as glucose, asthe perfusion 108 solution flows through the system 100, and in someembodiments, while it is in the reservoir 160. The maintenance solutions116/118 also include a supply of therapeutics and preservatives 118 forreducing ischemia and other re-perfusion related injuries to the heart102.

Both normal and retrograde flow modes are described in further detailbelow with reference to FIGS. 24A-26B.

According to the illustrative embodiment, the system 100 is primed priorto introducing an organ into the organ chamber assembly 104. Duringpriming, a priming solution (described below) is inserted into the organchamber 160 and pumped through the system 100. In one exemplarapplication, the priming occurs for a period of between about 5 andabout 20 minutes. The cannulation interfaces 162, 166 and 170 in theorgan chamber assembly 104 are bypassed to enable normal mode flow ofperfusion fluid 108 through the system 100, without the donor heart 102being present. Blood (or a synthetic blood substitute) is then loadedinto the reservoir 160. The blood may be the blood exsanguinated fromthe donor during harvesting of the heart 102 or obtained from typed andcross-matched banked blood. The system 100 then circulates the blood (orblood substitute) through the system 100 to heat, oxygenate, and filterit. Nutrients, preservatives and/or other therapeutics are provided viathe infusion pump 182 of the nutritional subsystem 115. Variousparameters may also be initialized and calibrated via the operatorinterface 146 during priming. Once the system 100 is runningappropriately, the pump rate can be decreased or brought to zero, andthe heart 102 can be cannulated into the organ chamber assembly 104. Thepump rate can then be increased. Priming of the system 100 is describedin further detail below with reference to the flow diagram of FIG. 29A.

As shown in FIG. 1, the system 100 also includes a plurality ofcompliance chambers 184, 186 and 188. The compliance chambers 184, 186and 188 are essentially small inline fluid accumulators with flexible,resilient walls designed to simulate the human body's vascularcompliance by aiding the system in more accurately mimicking blood flowin the human body, for example, by providing flow back-pressure and/orby filtering/reducing fluid pressure spikes due, for example, to flowrate changes and/or the pumping of the pump 106. According to theillustrative embodiment, the compliance chamber 184 is located betweenan output 112 a of the mode valve 112 and the reservoir 160 and operatesin combination with an adjustable clamp 190 during normal flow mode toprovide back pressure to the aorta 158 to cause perfusion fluid to flowinto the coronary sinus 155 to feed the heart 102. In the illustrativeembodiment, the fluid back-pressure provided to the aorta 158 is betweenabout 55 mmHg and about 85 mmHg, which is within an acceptablenear-physiologic range of mean aortic blood pressure (which is typicallybetween about 80 mmHg and about 100 mmHg). The back pressure to theaorta 158 aids the system 100 in simulating normal physiologicconditions. The compliance chamber 186 is located between an output 112b of the mode valve 112 and the pulmonary vein cannulation interface 170of the organ chamber assembly 104. The primary function of thecompliance chamber 186 is to provide back-pressure to the left atrium152 and to smooth pressure/flow spikes caused from the pumping action ofthe perfusion fluid pump 106, which delivers blood to the heart withoutcausing substantial fluid pressure spikes. In the illustrativeembodiment, the fluid back-pressure provided to the left atrium 152 isbetween about 0 mmHg to about 14 mmHg, which is approximately the sameas the left atrial pressure under normal physiologic conditions. Thecompliance chamber 188 is located between an output of a one way valve310 and an inlet 110 a of the heater 110. The primary function of thecompliance chamber 188 is also to smooth pressure/flow spikes caused bythe pumping action of the perfusion fluid pump 106 and to provide fluidback-pressure to the pulmonary artery 164. In the illustrativeembodiment, the fluid back-pressure provided to the pulmonary artery 164is between about 0 mmHg and about 25 mmHg, which is within an acceptablenear-physiologic range of mean arterial blood pressure (between about 0mmHg and about 12 mmHg).

The compliance chambers 184, 186 and 188 provide the benefits describedabove through their size and shape and the materials used in theirdesign. The chambers 184, 186 and 188 are sized to contain about 20 mlto about 100 ml of fluid 108, and they are shaped in an ovalconfiguration to allow them to receive fluid 108 and expand to dampenpressure spikes and to provide back-pressure to the heart 102. Incertain applications, the material used for the chambers 184, 186 and188 includes at least one flexible membrane, selected so that thechambers have a Shore A durametric hardness (ASTM D2240 00) of about 10(more flexible) to about 60 (less flexible), with certain preferredembodiments having a hardness of between about 30 (+/− about 8) andabout 50 (+/− about 8). In the illustrative embodiment, the compliancechamber 184 has a Shore A hardness of about 50 (+/− about 8) and thecompliance chamber 186 has a Shore A hardness of about 30 (+/− about 8).In the illustrative embodiment, the compliance chamber 188 has adual-layered configuration, with an inner chamber having a Shore Ahardness of about 50 (+/− about 8) and an outer sleeve having a Shore Ahardness of about 30 (+/− about 8). Alternatively, the inner chamber canhave a lower hardness (e.g., about 30, +/− about 8) and outer sleeve canhave a higher hardness (e.g., about 50, +/− about 8)).

Having provided an operational overview of the system 100, the organchamber assembly 104, the perfusion heater assembly 110, and a pump headinterface assembly 192 for interfacing with the pump 106 are nextdescribed in further detail. FIGS. 5A-5F depict various views of theillustrative organ chamber assembly 104 of FIG. 1. As shown most clearlyin FIGS. 5A-5D, the organ chamber assembly 104 includes a housing 194, aouter lid 196 and an intermediate lid 198. The housing includes a bottom194 e and one or more walls 194 a-194 d for containing the heart 102.The intermediate lid 198 covers an opening 200 to the housing 194 forsubstantially enclosing the heart 102 within the housing 194. As mostclearly shown in FIGS. 5E and 5F, the intermediate lid 198 includes aframe 198 a and a flexible membrane 198 b suspended within the frame 198a. The flexible membrane 198 b, preferably, is transparent but may beopaque, translucent, or substantially transparent. According to onefeature, the flexible membrane includes sufficient excess membranematerial to contact the heart 102 when contained within the housing 195.This feature enables a medical operator to touch/examine the heart 102indirectly through the membrane 198 b, or apply an ultrasound probe tothe heart 102 through the membrane 198 b, while maintaining sterility ofthe housing 195. The membrane 198 b may be made, for example, from anysuitable flexible polymer plastic, for example polyurethane. Themembrane 198 b may also have integrated electrically conductivepads/contacts 199 a and 199 b through which electrical activity of theheart may be sensed via electrodes such as the electrodes 142 and 144,and/or for through which defibrillation or pacing signals may bedelivered, as described more fully below. Alternatively, the contacts199 a and 199 b may be electrodes including all or a portion of thefunctionality of the electrodes 142 and 144. As shown in FIG. 5C, theouter lid 196 opens and closes over the intermediate lid 198independently from the intermediate lid 198. Preferably, the outer lid196 is rigid enough to protect the heart 102 from physical contact,indirect or indirect. The outer lid 196 and the chamber 194 may also bemade from any suitable polymer plastic, for example polycarbonate.

According to one implementation, the housing 194 includes two hingesections 202 a and 202 b, and the intermediate lid frame 198 a includestwo corresponding mating hinge sections 204 a and 204 b, respectively.The hinge sections 202 a and 202 b on the housing 194 interfit with thehinge sections 204 a and 204 b on the intermediate 11 d frame 198 a toenable the intermediate lid 198 to open and close relative to theopening 200 of the housing 194. As shown most clearly in FIGS. 5D and5F, the organ chamber assembly 104 also includes two latches 206 a and206 b for securing the intermediate lid 198 closed over the opening 200.As shown in FIGS. 5E and 5F, the latches 206 a and 206 b rotatably snapfit onto latch hinge section 208 a and 208 b, respectively, on the wall194 c of the housing 194. As shown most clearly in FIGS. 5A and 5E, theintermediate lid frame 198 a also includes a hinge section 210. Thehinge section 210 rotatably snap fits with a mating hinge section 212 onthe outer lid 196 to enable the outer lid 196 to open without openingthe intermediate lid 198. As shown best in FIGS. 5B, 5D and 5F, theouter lid 196 also includes two cutouts 214 a and 214 b for enabling thelatches 206 a and 206 b to clamp down on the edge 216 of theintermediate lid frame 198 a. As shown in FIGS. 5B, 5D and 5F, the organchamber assembly 104 also includes a latch 218, which rotatably snapfits onto a hinge part 220 on the wall 194 c of the housing 194. Inoperation, the latch 218 engages a tab 221 on the edge 225 of the outerlid 196 to secure the outer lid 196 closed over the intermediate lid198.

As shown most clearly in FIGS. 5E and 5F, the intermediate lid alsoincludes two gaskets 198 c and 198 d. The gasket 198 d interfits betweena periphery of the intermediate lid frame 198 a and a periphery of theouter lid 196 to form a fluid seal between the intermediate lid 198 andthe outer lid 196 when the outer lid 196 is closed. The gasket 198 cinterfits between an outer rim 194 f of the housing 194 and theintermediate lid frame 198 a to form a fluid seal between theintermediate lid 198 and the periphery 194 f of the housing 194 when theintermediate lid 198 is closed.

Optionally, the organ chamber assembly 104 includes a pad 222 or a sacassembly sized and shaped for interfitting over an inner bottom surface194 g of the housing 194. Preferably, the pad 222 is formed from amaterial resilient enough to cushion the heart 102 from mechanicalvibrations and shocks during transport, for example a closed-cell foam.According to one feature, the pad 222 includes a mechanism foradjustably positioning a pair of electrodes, such as the electrodes 142and 144 of FIG. 1. According to the illustrative embodiment, themechanism includes two through-apertures 224 a and 224 b for passingelectrical leads from the under side of the pad 222 to correspondingelectrodes 142 and 144 on the heart-contacting surface of the pad.Passing the electrical leads through the pad 222 to the electrodes 142and 144 enables the electrodes 142 and 144 to be adjustably positionedwithin the pad 222 to accommodate variously sized hearts. In otherembodiments, the mechanism may include, without limitation, one or moredifferently oriented slots, indentations, protrusions, throughapertures, partially through apertures, hooks, eyelets, adhesivepatches, or the like. In certain embodiments, the pad 222 may beconfigured with one or more sleeve-like structures that allow anelectrode to be inserted within the pad 222, thus providing amembrane-like surface of the pad 222 positioned between the electrodeand the heart 102.

In some illustrative embodiments, the pad 222 is configured as a padassembly, with the assembly including one or more electrodes, such asthe electrodes 142 and 144, adjustably located in or on the pad 222.According to one advantage, the pad/electrode configuration of theinvention facilitates contact between the electrodes and the heart 102placed on the pad 222, without temporarily or permanently suturing orotherwise mechanically connecting the electrodes to the heart 102. Theweight of the heart 102 itself can also help stabilize the electrodesduring transport. According to the illustrative embodiment, theelectrodes 142 and 144 include one or more sensors for monitoring one ormore electrical signals from the heart and/or defibrillators forproviding an electrical signal to the heart. As shown in FIGS. 1 and 5C,the organ chamber assembly 104 includes electrical interface connections235 a-235 b, which mount into the apertures 234 a-234 b, respectively,in the wall 194 b of the housing 194. A cover 226 is provided forprotecting the electrical interface connections 235 a-235 b when notbeing used.

As described below in further detail with reference to FIG. 15, theinterface connections 235 a and 235 b couple electrical signals, such asECG signals, from the electrodes 142 and 144 out of the housing 194, forexample, to the controller 194 and/or the operator interface 146. Asdescribed in further detail below with reference to FIG. 22A, theinterface connections 235 a and 235 b may also couple to adefibrillation source, which may be either provided by externalinstrumentation or through circuitry within the system 100, and whichcan send a defibrillation or pacing signal 143 through electrodes 142and 144 to the heart 102.

As shown most clearly in FIGS. 5E and 5F, the organ chamber assembly 104includes a resealable membrane interface 230, which mounts in aninterface aperture 232. The interface 230 includes a frame 230 a and aresealable polymer membrane 230 b mounted in the frame 230 a. Themembrane 230 b may be made of silicone or any other suitable polymer. Inoperation, the interface 230 is used to provide pacing leads, whennecessary, to the heart 102, without having to open the chamber lids 196and 198. The membrane 230 b seals around the pacing leads to maintain aclosed environment around the heart 102. The membrane 230 b also resealsin response to removing the pacing leads.

As shown in FIGS. 5A and 5B, the organ chamber assembly 104 includesapertures 228 a-228 c for receiving the aorta interface 162, thepulmonary artery interface 166 and the pulmonary vein interface 170,described above with reference to FIGS. 1-4, and below with reference toFIGS. 24A-28C. As shown in FIG. 5D, the organ chamber assembly 104 alsoincludes a drain 201 for draining perfusion fluid 108 out of the housing194 back into the reservoir 160, and mounting receptacles 203A-203 d formounting the organ chamber assembly 104 onto the single use module(shown at 634 in FIG. 19A).

FIGS. 6A-6F depict various views of the perfusion fluid heater assembly110 of FIG. 1. As shown in FIGS. 6A and 6B, the heater assembly 110includes a housing 234 having an inlet 110 a and an outlet 110 b. Asshown in both the longitudinal cross-sectional view of FIG. 6D and thelateral cross-sectional view of FIG. 6E, the heater assembly 110includes a flow channel 240 extending between the inlet 110 a and theoutlet 110 b. The heater assembly 110 may be conceptualized as havingupper 236 and lower 238 symmetrical halves. Accordingly, only the upperhalf is shown in an exploded view in FIG. 6F.

Referring now to FIGS. 6D-6F, the flow channel 240 is formed betweenfirst 242 and second 244 flow channel plates. The inlet 110 a flows theperfusion fluid into the flow channel 240 and the outlet 110 b flows theperfusion fluid out of the heater 110. The first 242 and second 244 flowchannel plates have substantially bioinert perfusion fluid 108contacting surfaces (which may contain a blood-product in certainembodiments) for providing direct contact with the perfusion fluidflowing through the channel 240. The fluid contacting surfaces may beformed from a treatment or coating on the plate or may be the platesurface itself. The heater assembly 110 includes first and secondelectric heaters 246 and 248, respectively. The first heater 246 islocated adjacent to and couples heat to a first heater plate 250. Thefirst heater plate 250, in turn, couples the heat to the first flowchannel plate 242. Similarly, the second heater 248 is located adjacentto and couples heat to a second heater plate 252. The second heaterplate 252 couples the heat to the second flow channel plate 244.According to the illustrative embodiment, the first 250 and second 252heater plates are formed from a material, such as aluminum, thatconducts and distributes heat from the first 246 and second 248 electricheaters, respectively, relatively uniformly. The uniform heatdistribution of the heater plates 250 and 252 enables the flow channelplates to be formed from a bioinert material, such as titanium, reducingconcern regarding its heat distribution characteristic.

Referring particularly to FIGS. 6E and 6F, the heater assembly 110 alsoincludes O-rings 254 and 256 for fluid sealing respective flow channelplates 242 and 244 to the housing 234 to form the flow channel 240.

The heater assembly 110 further includes first assembly brackets 258 and260. The assembly bracket 258 mounts on the top side 236 of the heaterassembly 110 over a periphery of the electric heater 246 to sandwich theheater 246, the heater plate 250 and the flow channel plate 242 betweenthe assembly bracket 258 and the housing 234. The bolts 262 a-262 j fitthrough corresponding through holes in the bracket 258, electric heater246, heater plate 250 and flow channel plate 242, and thread intocorresponding nuts 264 a-264 j to affix all of those components to thehousing 234. The assembly bracket 260 mounts on the bottom side 238 ofthe heater assembly 110 in a similar fashion to affix the heater 248,the heater plate 252 and the flow channel plate 244 to the housing 234.A resilient pad 268 interfits within a periphery of the bracket 258.Similarly, a resilient pad 270 interfits within a periphery of thebracket 260. A bracket 272 fits over the pad 268. The bolts 278 a-278 finterfit through the holes 276 a-276 f, respectively, in the bracket 272and thread into the nuts 280 a-280 f to compress the resilient pad 268against the heater 246 to provide a more efficient heat transfer to theheater plate 250. The resilient pad 270 is compressed against the heater248 in a similar fashion by the bracket 274.

As mentioned with respect to FIG. 1, and as also shown in FIG. 6A, theillustrative heater assembly 110 includes temperature sensors 120 and122 and dual-sensor 124. The dual sensor 124 in practice includes a dualthermistor sensor for providing fault tolerance, measures thetemperature of the perfusion fluid 108 exiting the heater assembly 110,and provides these temperatures to the controller 150. As described infurther detail below with respect to the heating subsystem 149 of FIG.13, the signals from the sensors 120, 122 and 124 may be employed in afeedback loop to control drive signals to the first 246 and/or second248 heaters to control the temperature of the heaters 256 and 248.Additionally, to ensure that heater plates 250 and 252 and, therefore,the blood contacting surfaces 242 and 244 of the heater plates 250 and252 do not reach a temperature that might damage the perfusion fluid,the illustrative heater assembly 110 also includes temperaturesensors/lead wires 120 and 122 for monitoring the temperature of theheaters 246 and 248, respectively, and providing these temperatures tothe controller 150. In practice, the sensors attached to sensors/leadwires 120 and 122 are RTD (resistance temperature device) based. As alsodiscussed in further detail with respect to FIG. 13, the signals fromthe sensors attached to sensors/lead wires 120 and 122 may be employedin a feedback loop to further control the drive signals to the first 246and/or second 248 heaters to limit the maximum temperature of the heaterplates 250 and 252. As a fault protection, there are sensors for each ofthe heaters 246 and 248, so that if one should fail, the system cancontinue to operate with the temperature at the other sensor.

As described in further detail below with respect to FIG. 13, the heater246 of the heater assembly 110 receives from the controller 150 drivesignals 281 a and 281 b (collectively 281) onto corresponding drive lead282 a. Similarly, the heater 248 receives from the controller 150 drivesignals 283 a and 283 b (collectively 283) onto drive lead 282 b. Thedrive signals 281 and 283 control the current to, and thus the heatgenerated by, the respective heaters 246 and 248. More particularly, asshown in FIG. 7, the drive leads 282 a includes a high and a low pair,which connect across a resistive element 286 of the heater 246. Thegreater the current provided through the resistive element 286, thehotter the resistive element 286 gets. The heater 248 operates in thesame fashion with regard to the drive lead 282 b. According to theillustrative embodiments, the element 286 has a resistance of about 5ohms. However, in other illustrative embodiments, the element may have aresistance of between about 3 ohms and about 10 ohms. As discussed inmore detail below with regard to FIGS. 11 and 13, the heaters 246 and248 may be controlled independently by the processor 150.

According to the illustrative embodiment, the heater assembly 110housing components are formed from a molded plastic, for example,polycarbonate, and weighs less than about one pound. More particularly,the housing 234 and the brackets 258, 260, 272 and 274 are all formedfrom a molded plastic, for example, polycarbonate. According to anotherfeature, the heater assembly is a single use disposable assembly.

In operation, the illustrative heater assembly 110 uses between about 1Watt and about 200 Watts of power, and is sized and shaped to transitionperfusion fluid 108 flowing through the channel 240 at a rate of betweenabout 300 ml/min and about 5 L/min from a temperature of less than about30° C. to a temperature of at least about 37° C. in less than about 30minutes, less than about 25 minutes, less than about 20 minutes, lessthan about 15 minutes or even less than about 10 minutes, withoutsubstantially causing hemolysis of cells, or denaturing proteins orotherwise damaging any blood product portions of the perfusion fluid.

According to one feature, the heater assembly 110 includes housingcomponents, such as the housing 234 and the brackets 258, 260, 272 and274, that are formed from a polycarbonate and weighs less than about 5lb. In other embodiments, the heater assembly may weigh less than about4 lb, less than about 3 lb, less than about 2 lb, or even less thanabout 1 lb. In the illustrative embodiment, the heater assembly 110 hasa length 288 of about 6.6 inches, not including the inlet 110 a andoutlet 110 b ports, and a width 290 of about 2.7 inches. The heaterassembly 110 has a height 292 of about 2.6 inches. The flow channel 240of the heater assembly 110 has a nominal width 296 of about 1.5 inches,a nominal length 294 of about 3.5 inches, and a nominal height 298 ofabout 0.070 inches. The height 298 and width 296 are selected to providefor uniform heating of the perfusion fluid 108 as it passes through thechannel 240. The height 298 and width 296 are also selected to provide across-sectional area within the channel 240 that is approximately equalto the inside cross-sectional area of fluid conduits that carry theperfusion fluid 108 into and/or away from the heater assembly 110. Inone configuration, the height 298 and width 296 are selected to providea cross-sectional area within the channel 240 that is approximatelyequal to the inside cross-sectional area of the inlet fluid conduit 792(shown below with reference to FIG. 25C) and/or substantially equal tothe inside cross-sectional area of the outlet fluid conduit 794 (shownbelow with reference to FIG. 24E).

Projections 257 a-257 d and 259 a-259 d are included in the heaterassembly 110 and are used to receive a heat-activated adhesive forbinding the heating assembly to the multiple-use unit 650 (referenced inFIG. 20A).

FIGS. 8A-8C show various views of a pump interface assembly 300according to an illustrative embodiment of the invention. FIG. 9 shows aperspective view of a pump-driver end of the perfusion fluid pumpassembly 106 of FIG. 1, and FIG. 10 shows the pump interface assembly300 mated with the pump-driver end of the perfusion fluid pump assembly106, according to an illustrative embodiment of the invention. Referringto FIGS. 8A-10, the pump interface assembly 300 includes a housing 302having an outer side 304 and an inner side 306. The interface assembly300 includes an inlet 308 and an outlet 310. As shown most clearly inthe bottom view of FIG. 8B and the exploded view of FIG. 8C, the pumpinterface assembly 300 also includes inner 312 and outer 314 O-ringseals, two deformable membranes 316 and 318, a doughnut-shaped bracket320, and half-rings 319 a and 319 b that fit between the o-ring 314 andthe bracket 320. The half-rings 319 a and 319 b may be made of foam,plastic, or other suitable material.

The inner O-ring 312 fits into an annular track along a periphery of theinner side 306. The first deformable membrane 316 mounts over the innerO-ring 312 in fluid tight interconnection with the inner side 306 of thehousing 302 to form a chamber between an interior side of the firstdeformable membrane 316 and the inner side 306 of the housing 302. Asecond deformable membrane 318 fits on top of the first deformablemembrane 316 to provide fault tolerance in the event that the firstdeformable membrane 316 rips or tears. Illustratively, the deformablemembranes 316 and 318 are formed from a thin polyurethane film (about0.002 inches thick). However, any suitable material of any suitablethickness may be employed. Referring to FIGS. 8A and 8B, the bracket 320mounts over the second deformable membrane 318 and the rings 319 a and319 b and affixes to the housing 302 along a periphery of the inner side306. Threaded fasteners 322 a-322 i attach the bracket 320 to thehousing 302 by way of respective threaded apertures 324 a-324 i in thebracket 320. As shown in FIG. 8B, the outer O-ring 314 interfits into anannular groove in the bracket 320 for providing fluid tight seal withthe pump assembly 106. Prior to inserting O-ring 314 into the annulargroove in bracket 320, the half-rings 319 a and 319 b are placed in thegroove. The O-ring 314 is then compressed and positioned within theannular groove in bracket 320. After being positioned within the annulargroove, the O-ring 314 expands within the groove to secure itself andthe half-rings 319 a and 319 b in place.

The pump interface assembly 300 also includes heat stake points 321a-321 c, which project from its outer side 304. As described in furtherdetail below with reference to FIGS. 21A-21C and 24A-24C, the points 321a-321 c receive a hot glue to heat-stake the pump interface assembly 300to a C-shaped bracket 656 of the single use disposable module chassis635.

As shown in FIG. 8C, the fluid outlet 310 includes an outlet housing 310a, an outlet fitting 310 b, a flow regulator ball 310 c and an outletport 310 d. The ball 310 c is sized to fit within the outlet port 310 dbut not to pass through an inner aperture 326 of the outlet 310. Thefitting 310 b is bonded to the outlet port 310 d (e.g., via epoxy oranother adhesive) to capture the ball 310 c between the inner aperture326 and the fitting 310 b. The outlet housing 310 a is similarly bondedonto the fitting 310 b.

In operation, the pump interface assembly 300 is aligned to receive apumping force from a pump driver 334 of the perfusion fluid pumpassembly 106 and translate the pumping force to the perfusion fluid 108,thereby circulating the perfusion fluid 108 to the organ chamberassembly 104. According to the illustrative embodiment, the perfusionfluid pump assembly 106 includes a pulsatile pump having a driver 334(described in further detail below with regard to FIG. 9), whichcontacts the membrane 318. The fluid inlet 308 draws perfusion fluid108, for example, from the reservoir 160, and provides the fluid intothe chamber formed between the inner membrane 316 and the inner side 306of the housing 302 in response to the pump driver moving in a directionaway from the deformable membranes 316 and 318, thus deforming themembranes 316 and 318 in the same direction. As the pump driver movesaway from the deformable membranes 316 and 318, the pressure head of thefluid 108 inside the reservoir 160 causes the perfusion fluid 108 toflow from the reservoir 160 into the pump assembly 106. In this respect,the pump assembly 106, the inlet valve 191 and the reservoir 160 areoriented to provide a gravity feed of perfusion fluid 108 into the pumpassembly 106. At the same time, the flow regulator ball 310 c is drawninto the aperture 326 to prevent perfusion fluid 108 from also beingdrawn into the chamber through the outlet 310. It should be noted thatthe outlet valve 310 and the inlet valve 191 are one way valves in theillustrated embodiment, but in alternative embodiments the valves 310and/or 191 are two-way valves. In response to the pump driver 334 movingin a direction toward the deformable membranes 316 and 318, the flowregulator ball 310 c moves toward the fitting 310 b to open the inneraperture 326, which enables the outlet 310 to expel perfusion fluid 108out of the chamber formed between the inner side 306 of the housing 302and the inner side of the deformable membrane 316. A separate one-wayinlet valve 191, shown between the reservoir 160 and the inlet 308 inFIG. 1, stops any perfusion fluid from being expelled out of the inlet308 and flowing back into the reservoir 160.

As discussed in further detail below with respect to FIGS. 18A-27B, incertain embodiments the organ care system 100 mechanically divides intoa disposable single-use unit (shown at 634 in FIGS. 19A-19C and 24A-25C)and a non-disposable multi-use unit (shown at 650 in FIG. 20A). In suchembodiments, the pump assembly 106 rigidly mounts to the multiple usemodule 650, and the pump interface assembly 300 rigidly mounts to thedisposable single use module 634. The pump assembly 106 and the pumpinterface assembly 300 have corresponding interlocking connections,which mate together to form a fluid tight seal between the twoassemblies 106 and 300.

More particularly, as shown in the perspective view of FIG. 9, theperfusion fluid pump assembly 106 includes a pump driver housing 338having a top surface 340, and a pump driver 334 housed within a cylinder336 of the housing 338. The pump driver housing 338 also includes adocking port 342, which includes a slot 332 sized and shaped for matingwith a flange 328 projecting from the pump interface assembly 300. Asshown in FIG. 10, the top surface 340 of the pump driver housing 338mounts to a bracket 346 on the non-disposable multiple use module unit650. The bracket 346 includes features 344 a and 344 b for abutting thetapered projections 323 a and 323 b, respectively, of the pump interfaceassembly 300. The bracket 346 also includes a cutout 330 sized andshaped for aligning with the docking port 342 and the slot 332 on thepump driver housing 338.

Operationally, the seal between the pump interface assembly 300 and thefluid pump assembly 106 is formed in two steps, illustrated withreference to FIGS. 9 and 10. In a first step, the flange 328 ispositioned within the docking port 342, while the tapered projections323 a and 323 b are positioned on the clockwise side next tocorresponding features 344 a and 344 b on the bracket 346. In a secondstep, as shown by the arrows 345, 347 and 349 in FIG. 9, the pumpinterface assembly 300 and the fluid pump assembly 106 are rotated inopposite directions (e.g., rotating the pump interface assembly 300 in acounter clockwise direction while holding the pump assembly 106 fixed)to slide the flange 328 into the slot 332 of the docking port 342. Atthe same time, the tapered projections 323 a and 323 b slide under thebracket features 344 a and 344 b, respectively, engaging inner surfacesof the bracket features 344 a and 344 b with tapered outer surfaces ofthe tapered projections 323 a and 323 b to draw the inner side 306 ofthe pump interface assembly 300 toward the pump driver 334 and tointerlock the flange 328 with the docking ports 342, and the taperedprojections 323 a and 323 b with the bracket features 344 a and 344 b toform the fluid tight seal between the two assemblies 300 and 106.

Having described the illustrative organ care system 100 from a system,operational and component point of view, illustrative control systemsand methods for achieving operation of the system 100 are nextdiscussed. More particularly, FIG. 11 depicts a block diagram of anillustrative control scheme for the system 100. As described above withreference to FIG. 1, the system 100 includes a controller 150 forcontrolling operation of the system 100. As shown, the controller 150connects interoperationally with the following six subsystems: anoperator interface 146 for assisting an operator in monitoring andcontrolling the system 100 and in monitoring the condition of the heart102; a data acquisition subsystem 147 having various sensors forobtaining data relating to the heart 102 and to the system 100, and forconveying the data to the controller 150; a power management subsystem148 for providing fault tolerant power to the system 100; a heatingsubsystem 149 for providing controlled energy to the heater 110 forwarming the perfusion fluid 108; a data management subsystem 151 forstoring and maintaining data relating to operation of the system 100 andwith respect to the heart 102; and a pumping subsystem 153 forcontrolling the pumping of the perfusion fluid 108 through the system100. It should be noted that although the system 100 is describedconceptually with reference to a single controller 150, the control ofthe system 100 may be distributed in a plurality of controllers orprocessors. For example, any or all of the described subsystems mayinclude a dedicated processor/controller. Optionally, the dedicatedprocessors/controllers of the various subsystems may communicate withand via a central controller/processor.

FIGS. 12-17J illustrate the interoperation of the various subsystems ofFIG. 11. Referring first to the block diagram of FIG. 12, the dataacquisition subsystem 147 includes sensors for obtaining informationpertaining to how the system 100 and the heart 102 is functioning, andfor communicating that information to the controller 150 for processingand use by the system 100. As described with respect to FIG. 1, thesensors of subsystem 147 include, without limitation: temperaturesensors 120, 122 and 124; pressure sensors 126, 128, and 130; flow ratesensors 134, 136 and 138; the oxygenation/hematocrit sensor 140; andelectrodes 142 and 144. The data acquisition subsystem 147 alsoincludes: a set of Hall sensors 388 and a shaft encoder 390 from theperfusion pump assembly 106; battery sensors 362 a-362 c for sensingwhether the batteries 352 a-352 c, respectively, are sufficientlycharged; an external power available sensor 354 for sensing whetherexternal AC power is available; an operator interface module batterysensor 370 for sensing a state of charge of the operator interfacemodule battery; and a gas pressure sensor 132 for sensing gas flow fromthe gas flow chamber 176. How the system 100 uses the information fromthe data acquisition subsystem 147 will now be described with regard tothe heating 149, power management 148, pumping 153, data management 151,and operator interface 146 subsystems, shown in further detail in FIGS.13-17J, respectively.

The heating subsystem 149 is depicted in the block diagram of FIG. 13.With continued reference also to FIG. 1, the heating subsystem 149controls the temperature of the perfusion fluid 108 within the system100 through a dual feedback loop approach. In the first loop 251 (theperfusion fluid temperature loop), the perfusion fluid temperaturethermistor sensor 124 provides two (fault tolerant) signals 125 and 127to the controller 150. The signals 125 and 127 are indicative of thetemperature of the perfusion fluid 108 as it exits the heater assembly110. The controller 150 regulates the drive signals 285 and 287 to thedrivers 247 and 249, respectively. The drivers 247 and 249 convertcorresponding digital level signals 285 and 287 from the controller 150to heater drive signals 281 and 283, respectively, having sufficientcurrent levels to drive the first 246 and second 248 heaters to heat theperfusion fluid 108 to within an operator selected temperature range. Inresponse to the controller 150 detecting that the perfusion fluidtemperatures 125 and 127 are below the operator-selected temperaturerange, it sets the drive signals 281 and 283 to the first 246 and second248 heaters, respectively, to a sufficient level to continue to heat theperfusion fluid 108. Conversely, in response to the controller 150detecting that the perfusion fluid temperatures 125 and 127 are abovethe operator-selected temperature range, it decreases the drive signals281 and 283 to the first 246 and second 248 heaters, respectively. Inresponse to detecting that the temperature of the perfusion fluid 108 iswithin the operator-selected temperature range, the controller 150maintains the drive signals 281 and 283 at constant or substantiallyconstant levels.

Preferably, the controller 150 varies the drive signals 281 and 283 insubstantially the same manner. However, this need not be the case. Forexample, each heater 246 and 248 may respond differently to a particularcurrent or voltage level drive signal. In such a case, the controller150 may drive each heater 246 and 248 at a slightly different level toobtain the same temperature from each. According to one feature, theheaters 246 and 248 each have an associated calibration factor, whichthe controller 150 stores and employs when determining the level of aparticular drive signal to provide to a particular heater to achieve aparticular temperature result. In certain configurations, the controller150 sets one of the thermistors in dual sensor 124 as the defaultthermistor, and will use the temperature reading from the defaultthermistor in instances where the thermistors give two differenttemperature readings. In certain configurations, where the temperaturereadings are within a pre-defined range, the controller 150 uses thehigher of the two readings. The drivers 247 and 249 apply the heaterdrive signals 281 and 283 to corresponding drive leads 282 a and 282 bon the heater assembly 110.

In the second loop 253 (the heater temperature loop), the heatertemperature sensors 120 and 122 provide signals 121 and 123, indicativeof the temperatures of the heaters 246 and 248, respectively, to thecontroller 150. According to the illustrated embodiment, a temperatureceiling is established for the heaters 246 and 248 (e.g., by default orby operator selection), above which the temperatures of the heaters 246and 248 are not allowed to rise. As the temperatures of the heaters 246and 248 rise and approach the temperature ceiling, the sensors 121 and123 indicate the same to the controller 150, which then lowers the drivesignals 281 and 283 to the heaters 246 and 248 to reduce or stop thesupply of power to the heaters 246 and 248. Thus, while a lowtemperature signal 125 or 127 from the perfusion fluid temperaturesensor 124 can cause the controller 150 to increase power to the heaters246 and 248, the heater temperature sensors 120 and 122 ensure that theheaters 246 and 248 are not driven to a degree that would cause theirrespective heater plates 250 and 252 to become hot enough to damage theperfusion fluid 108. According to various illustrative embodiments, thecontroller 150 is set to maintain the perfusion fluid temperature atbetween about 32° C. and about 37° C., or between about 34° C. and about36° C. According to a further illustrative embodiment, the controller150 is set to limit the maximum temperature of the heater plates 250 and252 to less than about 38° C., 39° C., 40° C., 41° C., or 42° C.

As can be seen, the second loop 253 is configured to override the firstloop 251, if necessary, such that temperature readings from temperaturesensors 120 and 122 indicating that the heaters 246 and 248 areapproaching the maximum allowable temperature override the effect of anylow temperature signal from the perfusion fluid temperature sensor 124.In this respect, the subsystem 149 ensures that the temperature of theheater plates 250 and 252 do not rise above the maximum allowabletemperature, even if the temperature of the perfusion fluid 108 has notreached the operator-selected temperature value. This override featureis particularly important during failure situations. For example, if theperfusion fluid temperature sensors 124 both fail, the second loop 253stops the heater assembly 110 from overheating and damaging theperfusion fluid 108 by switching control exclusively to the heatertemperature sensors 120 and 122 and dropping the temperature set pointto a lower value. According to one feature, the controller 150 takesinto account two time constants assigned to the delays associated withthe temperature measurements from the heaters 246 and 248 and perfusionfluid 108 to optimize the dynamic response of the temperature controls.

FIG. 14 depicts a block diagram of the power management system 148 forproviding fault tolerant power to the system 100. As shown, the system100 may be powered by one of four sources—by an external AC source 351(e.g., 60 Hz, 120 VAC in North America or 50 Hz, 230 VAC in Europe) orby any of three independent batteries 352 a-352 c. The controller 150receives data from an AC line voltage availability sensor 354, whichindicates whether the AC voltage 351 is available for use by the system100. In response to the controller 150 detecting that the AC voltage 351is not available, the controller 150 signals the power switchingcircuitry 356 to provide system power high 358 from one of the batteries352 a-352 c. The controller 150 determines from the battery chargesensors 362 a-362 c which of the available batteries 352 a-352 c is mostfully charged, and then switches that battery into operation by way ofthe switching network 356.

Alternatively, in response to the controller 150 detecting that theexternal AC voltage 351 is available, it determines whether to use theavailable AC voltage 351 (e.g., subsequent to rectification) forproviding system power 358 and for providing power to the user interfacemodule 146, for charging one or more of the batteries 352 a-352 c,and/or for charging the internal battery 368 of user interface module146, which also has its own internal charger and charging controller. Touse the available AC voltage 351, the controller 150 draws the ACvoltage 351 into the power supply 350 by signaling through the switchingsystem 364. The power supply 350 receives the AC voltage 351 andconverts it to a DC current for providing power to the system 100. Thepower supply 350 is universal and can handle any line frequencies orline voltages commonly used throughout the world. According to theillustrative embodiment, in response to a low battery indication fromone or more of the battery sensors 362 a-362 c, the controller 150 alsodirects power via the switching network 364 and the charging circuit 366to the appropriate battery. In response to the controller 150 receivinga low battery signal from the sensor 370, it also or alternativelydirects a charging voltage 367 to the user interface battery 368.According to another feature, the power management subsystem 148 selectsbatteries to power the system 100 in order of least-charged first,preserving the most charged batteries. If the battery that is currentlybeing used to power the system 100 is removed by the user, the powermanagement subsystem 148 automatically switches over to the nextleast-charged battery to continue powering the system 100.

According to another feature, the power management subsystem 148 alsoemploys a lock-out mechanism to prevent more than one of the batteries352 a-352 c from being removed from the system 100 at a given time. Ifone battery is removed, the other two are mechanically locked intoposition within the system 100. In this respect, the system 148 providesa level of fault tolerance to help ensure that a source of power 358 isalways available to the system 100.

The pumping subsystem 153 of FIG. 11 will now be described in furtherdetail with reference to FIGS. 15 and 16. More particularly, FIG. 15 isa conceptual block diagram depicting the illustrative pumping subsystem153, and FIG. 16 shows an exemplary ECG 414 of a heart 102 synchronizedwith an exemplary wave 385 depicting pumping output by the subsystem153. The ECG 414 shown in FIG. 16 has P, Q, R, S, T, and U peaks. Thepumping subsystem 153 includes the perfusion fluid pump 106interoperationally connected to the pump interface assembly 300, asdescribed in more detail above with reference to FIGS. 8A-10. As shownin FIG. 15, the controller 150 operates the pumping subsystem 153 bysending a drive signal 339 to a brushless three-phase pump motor 360using Hall Sensor feedback. The drive signal 339 causes the pump motorshaft 337 to rotate, thereby causing the pump screw 341 to move the pumpdriver 334 up and/or down. According to the illustrative embodiment, thedrive signal 339 is controlled to change a rotational direction androtational velocity of the motor shaft 337 to cause the pump driver 334to move up and down cyclically. This cyclical motion pumps the perfusionfluid 108 through the system 100.

In operation, the controller 150 receives a first signal 387 from theHall sensors 388 positioned integrally within the pump motor shaft 337to indicate the position of the pump motor shaft 337 for purposes ofcommutating the motor winding currents. The controller 150 receives asecond higher resolution signal 389 from a shaft encoder sensor 390indicating a precise rotational position of the pump screw 341. From thecurrent motor commutation phase position 387 and the current rotationalposition 389, the controller 150 calculates the appropriate drive signal339 (both magnitude and polarity) to cause the necessary rotationalchange in the motor shaft 337 to cause the appropriate vertical positionchange in the pump screw 341 to achieve the desired pumping action. Byvarying the magnitude of the drive signal 339, the controller 150 canvary the pumping rate (i.e., how often the pumping cycle repeats) and byvarying the rotational direction changes, the controller 150 can varythe pumping stroke volume (e.g., by varying how far the pump driver 334moves during a cycle). Generally speaking, the cyclical pumping rateregulates the pulsatile rate at which the perfusion fluid 108 isprovided to the heart 102, while (for a given rate) the pumping strokeregulates the volume of perfusion fluid 108 provided to the heart 102.

Both the rate and stroke volume affect the flow rate, and indirectly thepressure, of the perfusion fluid 108 to and from the heart 102. Asmentioned with regard to FIG. 1, the system includes three flow ratesensors 134, 136 and 138, and three pressure sensors 126, 128 and 130.As shown in FIG. 15, the sensors 134, 136, and 138 provide correspondingflow rate signals 135, 137 and 139 to the controller 150. Similarly, thesensors 126, 128 and 130 provide corresponding pressure signals 129, 131and 133 to the controller 150. The controller 150 employs all of thesesignals in feedback to ensure that the commands that it is providing tothe perfusion pump 106 have the desired effect on the system 100. Insome instances, and as discussed below in further detail with referenceto FIGS. 17A-17J, the controller 150 may generate various alarms inresponse to a signal indicating that a particular flow rate or fluidpressure is outside an acceptable range. Additionally, employingmultiple sensors enables the controller 150 to distinguish between amechanical issue (e.g., a conduit blockage) with the system 100 and abiological issue with the heart 102.

According to one feature of the invention, the pumping system 153 may beconfigured to control the position of the pump driver 334 during eachmoment of the pumping cycle to allow for finely tuned pumping rate andvolumetric profiles. This in turn enables the pumping system 153 tosupply perfusion fluid 108 to the heart with any desired pulsatilepattern. According to one illustrative embodiment, the rotationalposition of the shaft 337 is sensed by the shaft encoder 390 andadjusted by the controller 150 at least about 100 increments perrevolution. In another illustrative embodiment, the rotational positionof the shaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 1000 increments per revolution. Accordingto a further illustrative embodiment, the rotational position of theshaft 337 is sensed by the shaft encoder 390 and adjusted by thecontroller 150 at least about 2000 increments per revolution. Thevertical position of the pump screw 341 and thus the pump driver 334 iscalibrated initially to a zero or a ground position, corresponding to areference position of the pump screw 341.

According to the illustrative embodiment, the positional precision ofthe pumping subsystem 153 enables the controller 150 to preciselyregulate the pumping of the perfusion fluid 108 through the heart 102.This process of synchronizing the pulsatile flow of the perfusion fluidto the heart's natural rate is referred to herein as “r-wavesynchronization,” which is described with continued reference to FIGS.2, 15, and 16. A normally functioning heart has a two-phase pumpingcycle—diastole and systole. During the diastolic phase, also known asthe “resting phase,” the heart's atria 157 and 152 contract, causingvalves to open between the atria 157 and 152 and the ventricles 154 and156 to allow blood to flow into and load the ventricles 154 and 156.During the systolic phase, the loaded ventricles eject the blood, andthe atria 157 and 152 are opened and fill with blood. The cyclicalexpansion and contraction of the heart 102 during this process can berepresented by graphing the heart's ventricular ECG wave form, shown at414 in FIG. 16. FIG. 16 depicts the ECG waveform 414 synchronized withan exemplary wave 385 representative of a pumping output by thesubsystem 153.

The pumping subsystem 153 is configured to provide the maximum output ata time that will result in delivery of fluid 108 to the heart 102 at themost beneficial time. In the illustrated embodiment, in retrograde mode,the pumping subsystem 153 is configured to pump fluid 108 toward theheart 102 so that the maximum pump output 382 occurs during thediastolic phase of the heart, which begins after the S peak shown inFIG. 16 and is when the left ventricle 156 has finished ejectingperfusion fluid 108 through the aorta 158. Timing the pump output inthis manner allows the user to maximize the injection of perfusion fluid108 through the aorta 158 and into the coronary sinus 155. The timedpumping is accomplished by starting the pumping at point 377 on wave385, which is a point prior to point 382 and corresponds to the peak ofthe heart's r-wave pulse 380 and the middle of ventricular systole. Thepoint 377 is selected to account for time-delay between the time asignal is provided from the controller 150 to start pumping the fluidand the time of actual delivery of the pumped fluid 108 to the heart102. In another example, during normal flow mode where the left side ofthe heart fills and ejects perfusion fluid (as described in more detailwith reference to FIG. 24A), the controller 150 synchronizes the pumpingsubsystem 153 to start pumping at a fixed period of time after ther-wave 380, so as to match the natural filling cycle of the left atrium152. The synchronization may be adjusted and fine-tuned by the operatorthrough a pre-programmed routine in the operating software on the system100 and/or by manually operating the controls of the user interfacedisplay area 410, as described in more detail below in reference toFIGS. 17A-17J.

To achieve the synchronized pump output, the controller 150 predictswhen the heart's r-wave pulses 380 will occur and causes the pump topump at the appropriate time during the ECG 414. To make thisprediction, the controller 150 measures the length various r-wave pulses380 from the electrical signals 379 and 381 provided from the electrodes142 and 144, respectively. From these pulses, the controller 150 tracksthe time that elapses from one pulse 380 to the next, and uses thisinformation to calculate a running average of the length of timeseparating two sequential r-wave pulses. From this information, thecontroller 150 projects the time of the next r-wave (and from theprojection determines the time prior to or after that projected r-wavewhen the pumping should start to achieve optimal output delivery) byadding the average time separating two sequential r-wave pulses to thetime of the previous r-wave 380. Based on this running average ofseparation time between r-waves, the controller 150 has the option toadjust the time of pump output in relation to subsequent r-waves, asreflected in the movement of wave 385 to the left or the right along theECG 414 as signified by the arrow 383 in FIG. 16. Adjusting the wave 385thus allows the user to adjust and customize the timing of output by thepump 106 so as to optimize the filling of the heart. In addition, thepump 106 may also be adjusted to increase or decrease the pump strokevolume to customize the volume of fluid 108 provided by the pump 106,and this may be done either in concert with or independent of the r-wavesynchronization.

It should be noted that although the subsystem 153 particularlysynchronizes with the r-wave cycle 385, this need not be the case. Inalternative illustrative embodiments, the subsystem 153 may pump insynchronicity with any available characteristic of the heart, includingfluid pressures into or out of a particular chamber or vessel. Also, thesubsystem 153 may be programmed to pump in any arbitrary pattern,whether periodic or not.

Referring back to FIG. 11, the data management subsystem 151 receivesand stores data and system information from the various othersubsystems. The data and other information may be downloaded to aportable memory device and organized within a database, as desired by anoperator. The stored data and information can be accessed by an operatorand displayed through the operator interface subsystem 146.

Turning now to the operator interface subsystem 146, FIGS. 17A-17J showvarious illustrative display screens of the operator interface subsystem146. The display screens of FIGS. 17A-17J enable the operator to receiveinformation from and provide commands to the system 100. FIG. 17Adepicts a top level “home page” display screen 400 according to anillustrative embodiment of the invention. From the display screen 400 anoperator can access all of the data available from the data acquisitionsubsystem 147, and can provide any desired commands to the controller150. As described in more detail in reference to FIGS. 17B-17J, thedisplay screen 400 of FIG. 17A also allows the operator to access moredetailed display screens for obtaining information, providing commandsand setting operator selectable parameters.

With continued reference to FIG. 1, the display screen 400 includes adisplay area 402, which shows a number of numerical and graphicalindications pertaining to the operation of the system 100. Inparticular, the display area 402 includes a numerical reading of theaorta output pressure (AOP) 404 of the perfusion fluid 108 exiting theaorta interface 162 on the organ chamber assembly 104, a wave formdepiction 406 of the aortic fluid pressure (AOP) 404, and an AOP alarmimage 408 indicating whether the fluid pressure 404 is too high or toolow (the alarm 408 is shown as “off” in FIG. 17A). The display screen400 also includes a display area 410 having a numerical indication 412of the rate at which the heart 102 is beating, an ECG 414 of the heart102, a heart rate (HR) alarm image 416 indicating whether the HR 412exceeds or falls below operator set thresholds, and a time log 418indicating how long the system 100 has been running, including primingtime (discussed in further detail below with reference to FIG. 29A). Anumerical display 419 shows the amount of time for which the system 100has been supporting the heart 102. The indicator alarm 413 indicateswhen an operator preset time limit is exceeded.

The display screen 400 includes a number of additional display areas420, 424, 432, 438, 444, 450, 456, 460, 462, 466, 472, 480, and 482. Thedisplay area 420 shows a numerical reading of the pulmonary arterypressure (PAP) 422. The PAP 422 is an indication of the pressure of theperfusion fluid 108 flowing from the heart's pulmonary artery 164, asmeasured by the pressure sensor 130. The display area 420 also providesa PAP alarm indicator 424, which signals when the PAP 422 is outside anoperator preset range. The display area 426 indicates the temperature(Temp) 428 of the perfusion fluid 108 as it exits the heater 110. Thedisplay area 426 also includes a Temp alarm indicator 430, which signalsin response to the Temp 428 being outside of an operator preset range.The upper limit of the operator preset range is shown at 427. Thedisplay area 432 shows a numerical reading of the hematocrit (HCT) 434of the perfusion fluid 108, and an HCT alarm indicator 436 for signalingthe operator if the HCT 434 falls below an operator preset threshold.The display area 438 shows the oxygen saturation (SvO₂) 440 of theperfusion fluid 108. The display area 438 also includes a SvO₂ alarm 442for indicating if the SvO₂ 440 of the perfusion fluid 108 falls below anoperator preset threshold. The display area 444 indicates the aortaoutput flow rate (AOF) 446 of the perfusion fluid 108 as it flows out ofthe aorta 158. The AOF 446 is measured by the flow rate sensor 134. TheAOF alarm 448 indicates whether the flow rate 446 falls outside of anoperator preset range. The display area 450 shows the organ chamber flowrate (CF) 452. The CF 452 is an indication of the flow rate of theperfusion fluid 108 as it exits the organ chamber 104, as measured bythe flow rate sensor 136. The display area 450 also includes a CF alarm454, which signals in response to the CF 454 falling outside of anoperator preset range. The display area 456 includes a graphic 458 forindicating when a file transfer to the memory card is occurring.

The display area 460 shows a graphical representation 459 of the degreeto which each of the batteries 352 a-352 c (described above withreference to FIG. 14) is charged. The display area 460 also provides anumerical indication 461 of the amount of time remaining for which thebatteries 352 a-352 c can continue to run the system 100 in a currentmode of operation. The display area 462 identifies whether the operatorinterface module 146 is operating in a wireless 464 fashion, along witha graphical representation 463 of the strength of the wirelessconnection between the operator interface module 146 and the remainderof the system 100. The display area 462 also provides graphicalindication 467 of the charge remaining in the operator interface modulebattery 368 (described above with reference to FIG. 14) and a numericalindication 465 of the amount of time remaining for which the operatorinterface module battery 368 can support it in a wireless mode ofoperation. The display area 466 indicates the flow rate 468 of oxygenfrom the gas flow chamber 176. It also provides a graphical indication469 of how full an onboard oxygen tank is, and a numerical indication470 of the amount of time remaining before the onboard oxygen tank runsout. The display area 472 shows the heart rate of the heart 102, and theamount of time 476 for which the heart 102 has been cannulated onto thesystem 100. This field is duplicative of the field 419 mentioned above.The display areas 480 and 482 show the current time and date,respectively, of operation of the system 100.

Actuating a dial (or mouse, or other control device), such as the dial626 shown in FIG. 18A, on the operator interface 146 opens aconfiguration menu 484, such as shown in the display screen 401 of FIGS.17B. As shown, accessing the configuration menu 484 covers the displayareas 402 and 410 so they no longer show the graphical depictions of thepressure 406 and the heart rate 414, but continue to display criticalalpha/numeric information. As also shown, all other display areas remainunchanged. This enables an operator to adjust operation of the system100 while continuing to monitor critical information. According to onefeature, the configuration menu 484 allows the operator to pre-programdesired operational parameters for the system 100. Using the displayscreen 401, the operator can view/edit working and diastolic (orretrograde) mode alarms by selecting the fields 488 and 490,respectively. The operator can set particular ECG and LAP graphicaloptions by selecting the fields 492 and 494. Additionally, the operatorcan set oxygen flow rate and perfusion fluid temperature by selectingthe fields 496 and 498, respectively. Selecting the field 500 enablesthe operator to set the time and date, while selecting the field 502enables the operator to select the language in which information isdisplayed. At the bottom of the display field 484, the operator has theoption to return 504 to the display screen 400, cancel 506 any changesmade to operational settings, save 508 the changes as new defaults, orreset 510 the operational settings to factory defaults.

Referring to FIGS. 17C-17D, selecting the view/edit working mode alarmsfield 488 causes the working mode alarm dialog 512 of FIG. 17D to openwithin the display field 484 of FIG. 17C. The working mode dialog 512displays the parameters associated with normal flow mode (describedabove with reference to FIGS. 1 and 3) and includes a field for settingnumerical thresholds for each of the normal flow mode alarms. Morespecifically, the dialog 512 includes: CF alarm field 514; PAP alarmfield 516; AOP alarm field 518; LAP alarm field 520; perfusion fluidTemp alarm field 524; SvO₂ alarm field 526; HCT alarm field 528; and HRalarm field 530. By selecting a particular alarm field and actuating theup 532 and/or down 534 arrows, a operator can adjust the acceptableupper and/or lower thresholds for each of the parameters associated witheach of the alarms. The dialog 512 also includes alarm graphics 536a-536 i, each of which being associated with a particular normal flowmode alarm. The operator can enable/disable any of the above normal flowmode alarms by selecting the associated alarm graphic 536 a-536 i. Anychanges made using the dialog 512 are reflected in corresponding fieldsin the display screen 400 of FIG. 17A.

Referring to FIGS. 17A, 17B and 17E, selecting the view/edit non-workingmode alarms field 490 causes the resting mode alarm dialog 538 of FIG.17E to open within the display field 484 of FIG. 17C. The resting modedialog 538 displays the parameters associated with retrograde flow mode(described above with reference to FIGS. 1 and 4) and includes a fieldfor setting numerical thresholds for each of the retrograde flow modealarms. According to the illustrative embodiment, the available alarmsfor the normal and retrograde flow modes are similar, but notnecessarily the same. Additionally, even for those that are the same,the thresholds may differ. Accordingly, the invention enables theoperator to select different alarms and/or different thresholds for eachflow mode of operation. More specifically, the dialog 538 includes: CFalarm field 540; PAP alarm field 542; AOF alarm field 544; AOP alarmfield 546; LAP alarm field 548; perfusion fluid Temp alarm field 550;SvO₂ alarm field 552; HCT alarm field 556; and HR alarm field 558. Byselecting a particular alarm field and actuating the up 560 and/or down562 arrows, an operator can adjust the acceptable numerical upper and/orlower thresholds for each of the parameters associated with each of thealarms. The dialog 538 also includes alarm graphics 564 a-564 i, each ofwhich being associated with a particular normal flow mode alarm. Theoperator can enable/disable any of the above normal flow mode alarms byselecting the associated alarm graphic 564 a-564 i. As is the case ofthe dialog 512, any changes made using the dialog 538 are reflected incorresponding fields in the display screen 400 of FIG. 17A. In oneimplementation, the system 100 may be configured to automatically switchbetween sets of alarm limits for a given flow mode upon changing theflow mode.

Referring to FIGS. 17A, 17B, 17F and 17G, the operator interface 146also provides graphical mechanisms for adjusting various parameters. Forexample, as noted above in reference to FIG. 16, one advantage of theuser display area 402 is that it allows the operator to monitor (andadjust) the pumping of the subsystem 153. Display area 410 identifiesthe ECG waveform 414 of the heart 102, and display 402 shows in waveform 406 the pressure of fluid flowing through the aorta. In these twodisplays the operator can monitor the effect of the pumping profile onthe heart's EGC 414, which allows the user to adjust the stroke volumeof the pumping subsystem 153, to adjust the rate of the pumpingsubsystem 153 (and thus the flow-rate of the fluid 108 being pumpedthrough the system 100), to manually impose, or adjust a time of, firingof the subsystem (e.g., by imposing a fixed delay between the r-wave 380and the beginning of the pumping cycle), or to automatically program thepumping subsystem 153 to pump at a pre-determined time along the heart'sECG waveform 414, as needed to properly fill the heart according towhether the heart is being perfused in retrograde or normal mode. Thesepumping adjustments may be made by use of the various graphical framesof the operator interface 146. By way of example, in response to aoperator selecting the ECG graphic frame option 492 located in thedisplay field 484 of the display screen 401, the operator interface 146displays the dialog 568 of FIG. 17F. The dialog 568 shows a graphicalrepresentation 572 of the ECG 414 along with a cursor 570. The positionof the cursor 570 indicates the point at which the pumping subsystem 153will initiate an output pumping stroke (i.e., the portion of the pumpingcycle at which the pump motor 106 will push perfusion fluid 108 to theheart 102) relative to the ECG 414 of the heart 102. By rotating amechanical knob 626 (shown in FIGS. 18A and 18B) on the operatorinterface 146, the operator moves the position of the cursor 570 toadjust when the pumping subsystem 153 will initiate the output pumpingstroke relative to the r-wave pulse 380. As described above with regardto FIGS. 15 and 16, the pumping subsystem 153 receives an r-wave signal380 from the ECG sensors 142 and 144. The pumping subsystem 153 uses ther-wave signal 380 along with the pumping adjustment information from thecursor 570 to synchronize perfusion fluid pumping with the beating ofthe heart 102. In another example, in response to the operator pressingthe pump adjust button 625, the operator interface 146 displays thedialog 574 of FIG. 17G. From the dialog 574, the operator can select thepointer 576 and rotate the knob 626 to turn the pump motor 106 on andoff. Additionally, the operator can select the bar graphic 578 androtate the knob 626 to adjust the volume of fluid being pumped, which isdisplayed in liters/minute.

The operator interface 146 also provides a plurality of warning/remindermessages. By way of example, in FIG. 17H, the operator interface 146displays a message to remind the operator to connect to AC power torecharge the batteries. This message appears, for example, in responseto the controller 150 detecting an impending low battery condition. Theoperator interface 146 displays the message of FIG. 17I to confirm thatthe user wishes to enter standby mode and to remind the operator toinsert a portable memory device, such as magnetic or optical disk, aportable disk drive, a flash memory card or other suitable memorydevice, to download and store information regarding a particular use ofthe system 100. The operator interface 146 displays the error messages,such as the error message of FIG. 17J, in response to an identifiablefault occurring. The error messages of FIG. 17J include, for example,error information 580 to aid a service technician in diagnosing and/orrepairing the fault.

Having described an illustrative control systems and methods forachieving operation of the system 100, illustrative mechanical featuresof the system 100 will now be discussed, along with an illustrativedivision of components between the single use disposable module 634 andmultiple use module 650 units. More particularly, FIGS. 18A-18B show amechanical implementation 600 of the system of FIG. 1, according to anillustrative embodiment of the invention. As shown, the illustrativeimplementation 600 includes a housing 602 and a cart 604. The housing602 conceptually divides into upper 602 a and lower 602 b housingsections, and includes front 606 a, rear 606 b, left 606 c, and right606 d sides. The cart 604 includes a platform 608 and wheels 610 a-610 dfor transporting the system 600 from place to place. A latch 603 securesthe housing 602 to the cart 604. To further aid in portability, thesystem 600 also includes a handle 610 hinge mounted to the upper section602 a of the left side 606 c of the housing 602, along with two rigidlymounted handles 612 a and 612 b mounted on the lower section 602 b ofthe left 606 c and right 606 d sides of the housing 602.

The housing 602 further includes a removable top 614, and a front panel615 having an upper panel 613, and a mid panel 616 hinged to a lowerpanel 617 by hinges 616 a and 616 b. The top 614 includes handles 614 aand 614 b for aiding with removal. In the illustrated embodiment, theupper panel 613 is screwed, bolted or otherwise adjoined to the top 614,such that removal of the top 614 also removes panel 613.

As shown in FIG. 18A, the system 600 includes an AC power cable 618,along with a frame 620 for securing the power cable 618, both located onthe lower section 602 b of the left side 606 c of the housing 602. Asoftware reset switch 622, also located on the lower section 602 b ofthe left side 602 c, enables an operator to restart the system softwareand electronics.

As shown in FIGS. 18A and 18B, the implementation 600 also includes theoperator interface module 146, along with a cradle 623 for holding theoperator interface module 146. The operator interface module 146includes a display 624 for displaying information to an operator, forexample, by way of the display screens of FIGS. 17A-17J. As mentionedabove, the operator interface module 146 also includes a rotatable anddepressible knob 626 for selecting between the various parameters anddisplay screens of FIGS. 17A-17J. The knob 626 may also be used to setparameters for automatic control of the system 100, as well as toprovide manual control over the operation of the system 100. Forexample, the knob 626 may be used to provide instructions to thecontroller 150 to increase perfusion fluid flow rates, gas flow rates,etc. As also discussed above with regard to FIGS. 1, 14 and 17A-17J, theoperator interface module 146 includes its own battery 368 and may beremoved from the cradle 623 and used in a wireless mode. While in thecradle 623, power connections enable the operator interface module 146to be charged. As shown, the operator interface module also includescontrol buttons 625 for controlling the pump, silencing or disablingalarms, entering or exiting standby mode, entering or adjusting ECGsynchronization mode, and starting the perfusion clock, which initiatesthe display of data obtained during organ care.

As shown in FIG. 18B, the illustrative implementation 600 also includesa battery compartment 628 and an oxygen tank bay 630, both located onthe lower section 602 b of the right side 606 d of the housing 602. Asshown, the battery compartment 628 houses the three system batteries 352a-352 c, described above with regard to FIG. 14. According to onefeature, the battery compartment 626 includes three battery locks 632a-632 c. As described above with respect to FIG. 14, the battery locks632 a-632 c interoperate mechanically so that only one of the threebatteries 352 a-352 c may be removed at any given time.

The disposable module 634 and the multiple use unit 650 are constructedof material that is durable yet light-weight. In some illustrativeembodiments, polycarbonate plastic is used to form one or more of thecomponents of the units 634 and 650. To further reduce the weight, thechassis 635 and the multiple use module chassis 602 are formed from lowweight materials such as, for example, carbon fiber epoxy composites,polycarbonate ABS-plastic blend, glass reinforced nylon, acetal,straight ABS, aluminum or magnesium. According to one illustrativeembodiment, the weight of the entire system 600 is less than about 85pounds, including the multiple use module, heart, batteries, gas tank,and priming, nutritional, preservative and perfusion fluids, and lessthan about 50 pounds, excluding such items. According to anotherillustrative embodiment, the weight of the disposable module 634 is lessthan about 12 pounds, excluding any solutions. According to a furtherillustrative embodiment, the multiple use module 650, excluding allfluids, batteries 352 a-352 c and oxygen supply 172, weighs less thanabout 50 pounds.

With continued reference to FIGS. 19A-19C, various views are shown ofthe implementation 600 of FIGS. 18A and 18B with the top 614 and upperfront panel 613 removed and the front mid panel 616 open, according toan illustrative embodiment of the invention. With reference to FIGS.19A-19C, the system 100 is structured as a single use disposable module634 (shown and described in detail below with reference to FIGS.24A-25C) and a multiple use module 650 (shown without the single usemodule in FIG. 20). As discussed in further detail below, according toone feature of the illustrative embodiment, all of the blood contactingcomponents of the system 100 are included in the single use disposablemodule 634 so that after a use, the entire single use module 634 may bediscarded, a new module 634 installed, and the system 100 available foruse again within a very brief amount of time.

According to the illustrative embodiment, the single use module 634includes a chassis 635 for supporting all of the components of thesingle use module 634. As described in more detail with regard to FIGS.24A-25C, the components of the single use module 634 include the organchamber assembly 104, described above in detail with respect to FIGS.5A-5F, the perfusion fluid reservoir 160, the oxygenator 114, theperfusion fluid pump interface 300, and all of the various fluid flowconduits and peripheral monitoring components 633.

As shown in FIGS. 19A-20A, with the top 614 removed and the front panel616 open, an operator has easy access to many of the components of thedisposable 634 and multiple use 650 modules. For example, the operatormay install, remove and view the levels of the nutrient 116 andpreservative 118 supplies of the nutritional subsystem 115. The operatormay also control operation of the nutrient 116 and preservative 118infusion pump 182. The operator may also cannulate an organ, such as theheart 102, into the organ chamber assembly 104. As described in detailbelow with reference to FIGS. 21A-21C, this configuration also providesthe operator with sufficient access to install and/or remove the singleuse module 634 to/from the multiple use module 650.

FIG. 20A shows a front perspective view of the multiple use module 650with the single use module 634 removed. As shown, the multiple usemodule 650 includes: the cart 604; the lower section 602 b of thehousing 602, along with all of the components externally mounted to it,along with those contained therein (described in further detail below,with reference to FIGS. 21A-21C and 23A-23C); the upper section 602 a ofthe housing 602 and all of the components externally mounted to it,including the top cover 614, the handles 610, 612 a, and 612 b, and thefront panel 616; the operator interface module 146; and the perfusionfluid pump motor assembly 106. As described in detail below withreference to FIGS. 21A-21C, the multiple use module 650 also includes abracket assembly 638 for receiving and locking into place the single usemodule 534.

As shown in FIG. 20A and described in further detail below withreference to FIGS. 22A-22C, the multiple use module 650 also includes afront-end interface circuit board 636 for interfacing with a front-endcircuit board (shown in FIG. 24D at 637) of the disposable module 634.As also described in detail with reference to FIGS. 22A-22C, power anddrive signal connections between the multiple use module 650 and thedisposable module 634 are made by way of corresponding electromechanicalconnectors 640 and 647 on the front end interface circuit board 636 andthe front end circuit board 637, respectively. By way of example, thefront-end circuit board 637 receives power for the disposable module 634from the front-end interface circuit board 636 via the electromechanicalconnectors 640 and 647. The front end circuit board 637 also receivesdrive signals for various components (e.g., the heater assembly 110, andthe oxygenator 114) from the controller 150 via the front-end interfacecircuit board 636 and the electromechanical connectors 640 and 647. Thefront-end circuit board 637 and the front-end interface circuit board636 exchange control and data signals (e.g., between the controller 150and the disposable module 134) by way of optical connectors (shown inFIG. 22B at 648). As described in more detail with reference to FIGS.22A-22F, the connector configuration employed between the front-end 637and front-end interface 636 circuit boards ensures that critical powerand data interconnections between the single and multiple use modules634 and 650, respectively, continue to operate even during transportover rough terrain, such as may be experienced during organ transport.

As shown in FIG. 20A, according to another feature, the upper section602 a of the housing 602 includes a fluid tight basin 652, which isconfigured to capture any perfusion fluid 108 and/or nutritional 116and/or preservative 118 solution that may inadvertently leak. The basin652 also prevents any leaked fluid 108 or solution 116/118 from passinginto the lower section 602 b of the housing 602. In this way, the basin652 shields the electronic components of the system 100 from any suchleaked fluid 108 or solution 116/118. Shielded components include, forexample, the power board 720 shown in and discussed in further detailbelow with reference to FIGS. 23C and 23D. The basin 652 includes asection 658, which extends over and shields the perfusion fluid pump 106from any inadvertently leaked fluid. According to another feature, thebasin 652 is sized to accommodate the entire volume of perfusion fluid108 (including the maintenance solutions 116/118) contained within thesystem 100 at any particular time.

Referring also to FIG. 20B, according to a further feature of theillustrative embodiment, an outer side 659 of the pump covering portion658 of the basin 652 includes a slot 660. As described in further detailbelow with reference to FIGS. 21A-21C and 24A, the slot 660 engages witha projection 662 on the single use module 634 during installation of thesingle use module 634 into the multiple use module 650.

Turning now to the installation of the single use module 634 into themultiple use module 650, FIG. 21A shows a detailed view of theabove-mentioned bracket assembly 638 located on the multiple use module650 for receiving and locking into place the single use module 634. FIG.21B shows a side perspective view of the single use module 634 beinginstalled onto the bracket assembly 638 and into the multiple use module650, and FIG. 21C shows a side view of the single use module 634installed within the multiple use module 650. With reference to FIGS.21A and 21B, the bracket assembly 638 includes two mounting brackets 642a and 642 b, which mount to an internal side of a back panel 654 of theupper housing section 602 a via mounting holes 644 a-644 d and 646 a-646d, respectively. A cross bar 641 extends between and rotatably attachesto the mounting brackets 642 a and 642 b. Locking arms 643 and 645 arespaced apart along and radially extend from the cross bar 641. Eachlocking arm 643 and 645 includes a respective downward extending lockingprojection 643 a and 645 b. A lever 639 attaches to and extends radiallyupward from the cross bar 641. Actuating the lever 639 in the directionof the arrow 651 rotates the locking arms 643 and 645 toward the back606 b of the housing 602. Actuating the lever 639 in the direction ofthe arrow 653 rotates the locking arms 643 and 645 toward the front 606a of the housing 602.

As described above with respect to FIG. 10, the perfusion pump interfaceassembly 300 includes four projecting heat staking points 321 a-321 d.As shown in FIG. 24A, during assembly, the projections 321 a-321 d arealigned with corresponding apertures 657 a-657 d and heat staked throughthe apertures 657 a-657 d into the projections 321 a-321 d to rigidlymount the outer side 304 of the pump interface assembly 300 onto theC-shaped bracket 656 of the single use module chassis 635.

With reference to FIGS. 10, 20B, 21A, 21B and 24A, during installation,in a first step, the single use module 634 is lowered into the multipleuse module 650 while tilting the single use module 634 forward (shown inFIG. 21B). This process slides the projection 662 of FIG. 24A into theslot 660 of FIG. 20B. As shown in FIG. 10, it also positions the flange328 of the pump interface assembly 300 within the docking port 342 ofthe perfusion pump assembly 106, and the tapered projections 323 a and323 b of the pump interface assembly 300 on the clockwise side ofcorresponding ones of the features 344 a and 344 b of the pump assemblybracket 346. In a second step, the single use module 634 is rotatedbackwards until locking arm cradles 672 and 674 of the single use modulechassis 635 engage projections 643 and 645 of spring-loaded locking arm638, forcing the projections 643 and 645 to rotate upward (direction651), until locking projections 643 a and 645 a clear the height of thelocking arm cradles 672 and 674, at which point the springs cause thelocking arm 638 to rotate downward (direction 653), allowing lockingprojections 643 a and 645 a to releasably lock with locking arm cradles672 and 674 of the disposable module chassis 635. This motion causes thecurved surface of 668 of the disposable module chassis projection 662 ofFIG. 24A to rotate and engage with a flat side 670 of the basin slot 660of FIG. 20B. Lever 639 can be used to rotate the locking arm 638 upwards(direction 651) to release the single use module 635.

As shown in FIG. 10, this motion also causes the pump interface assembly300 to rotate in a counterclockwise direction relative to the pumpassembly 106 to slide the flange 328 into the slot 332 of the dockingport 342, and at the same time, to slide the tapered projections 323 aand 323 b under the respective bracket features 344 a and 344 b. As thetapered projections 323 a and 323 b slide under the respective bracketfeatures 344 a and 344 b, the inner surfaces of the bracket features 344a and 344 b engage with the tapered outer surfaces of the taperedprojections 323 a and 323 b to draw the inner side 306 of the pumpinterface assembly 300 toward the pump driver 334 to form the fluidtight seal between the pump interface assembly 300 and the pump assembly106. The lever 639 may lock in place to hold the disposable module 634securely within the multiple use module 650.

As mentioned briefly above with reference to FIG. 20A, interlocking thesingle use module 374 into the multiple use module 650 forms bothelectrical and optical interconnections between the front end interfacecircuit board 636 on the multiple use module 650 and the front endcircuit board 637 on the single use module 634. The electrical andoptical connections enable the multiple use module 650 to power, controland collect information from the single module 634. FIG. 22A is aconceptual drawing showing various optical couplers andelectromechanical connectors on the front end circuit board 637 of thesingle-use disposable module 634 used to communicate with correspondingoptical couplers and electromechanical connectors on the front endinterface circuit board 636 of the multiple use module 650. Since thiscorrespondence is one for one, the various optical couplers andelectromechanical connectors are described only with reference to thefront end circuit board 637, rather than also depicting the front endcircuit board 650.

According to the illustrative embodiment, the front end circuit board637 receives signals from the front end interface circuit board 636 viaboth optical couplers and electromechanical connectors. For example, thefront end circuit board 637 receives power 358 (also shown in FIG. 14)from the front end interface circuit board 636 via the electromechanicalconnectors 712 and 714. The front end circuit board 637 the power to thecomponents of the single use module 634, such as the various sensors andtransducers of the single use module 634. Optionally, the front endcircuit board 637 converts the power to suitable levels prior todistribution. The front end interface circuit board 636 also providesthe heater drive signals 281 a and 281 b of FIG. 13 to the applicableconnections 282 a on the heater 246 of FIG. 6E via the electromechanicalconnectors 704 and 706. Similarly, the electromechanical connectors 708and 710 couple the heater drive signals 283 a and 283 b of FIG. 13 tothe applicable connections in 282 b of the heater 248. The front-endcircuit board 637 may receive a defibrillation command from the frontend interface circuit board 636 via the electromechanical connector 687.In response, the front end circuit board 637 generates thedefibrillation signal 143 having suitable current and voltage levels,and as shown in FIG. 5E, couples the signal 143 to the organ chamberassembly 104 via the electrical interface connections 235 a-235 b.

In another illustrative embodiment, the defibrillation command can beprovided from an external source (not shown), rather than through thecircuit board 636. As an example, and with reference to FIG. 5E and FIG.1, an external defibrillation device can be plugged into the electricalcoupler 613 shown in FIG. 24E, which is connected to the electricalinterface connections 235 a-235 b. The external defibrillation devicesends a defibrillation signal 143 through the coupler 613 and theinterface connections 235 a and 235 b to electrodes 142 and 144. Theelectrodes 142 and 144 then deliver the signal 143 to the heart 102.This alternative embodiment allows the user to provide defibrillation(and pacing) without passing the signal 143 through the circuit boards618, 636, and 637. An exemplary external defibrillation device mayinclude the Zoll M-Series Portable Defibrillator.

According to the illustrative embodiment, the front end circuit board637 receives signals from temperature, pressure, fluid flow-rate,oxygentation/hematocrit and ECG sensors, amplifies the signals, convertsthe signals to a digital format and provides them to the front-endinterface circuit board 636 by way of optical couplers. For example, thefront end circuit board 637 provides the temperature signal 121 from thesensor 120 on the heater plate 250 (shown in FIGS. 6A and 13) to thefront end interface circuit board 636 by way of the optical coupler 676.Similarly, the front end circuit board 637 provides the temperaturesignal 123 from the sensor 122 on the heater plate 252 (shown in FIGS.6A and 13) to the front end interface circuit board 636 by way of theoptical coupler 678. The front end circuit board 637 also provides theperfusion fluid temperature signals 125 and 127 from the thermistorsensor 124 (shown in FIGS. 6A and 13) to the front end interface circuitboard 636 via respective optical couplers 680 and 682. Perfusion fluidpressure signals 129, 131 and 133 are provided from respective pressuretransducers 126, 128 and 130 to the front end interface circuit board636 via respective optical couplers 688, 690 and 692. The front endcircuit board 637 also provides perfusion fluid flow rate signals 135,137 and 139 from respective flow rate sensors 134, 136 and 138 to thefront end interface circuit board 636 by way of respective opticalcouplers 694, 696 and 698. Additionally, the front end circuit board 637provides the oxygen saturation 141 and hematocrit 145 signals from theoxygen saturation sensor 140 to the front end interface circuit board636 by way of respective optical couplers 700 and 702.

In other illustrative embodiments, one or more of the foregoing sensorsare wired directly to the main system board 718 (described below withreference to FIG. 23D) for processing and analysis, thus by-passing thefront-end interface board 636 and front-end board 637 altogether. Suchembodiments may be desirable where the user prefers to re-use one ormore of the sensors prior to disposal. In one such example, the flowrate sensors 134, 136 and 138 and the oxygen and hematocrit sensor 140are electrically coupled directly to the system main board 718 throughelectrical coupler 611 shown in FIG. 23C, thus by-passing any connectionwith the circuit boards 636 and 637.

As described above with respect to FIGS. 11-16, the controller 150employs the signals provided to the front end interface circuit board636, along with other signals, to transmit data and otherwise controloperation of the system 100. As described with respect to FIGS. 17A-17J,the controller 150 also displays sensor information, and may display tothe operator various alarms relating to the sensor information by way ofthe operator interface module 146.

FIG. 22B illustrates the operation of an exemplary electromechanicalconnector pair of the type employed for the electrical interconnectionsbetween the circuit boards 636 and 637. Similarly, FIG. 22C illustratesthe operation of an optical coupler pair of the type employed for theoptically coupled interconnections between the circuit boards 636 and637. One advantage of both the electrical connectors and opticalcouplers employed is that they ensure connection integrity, even whenthe system 100 is being transported over rough terrain, for example,such as being wheeled along a tarmac at an airport, being transported inan aircraft during bad weather conditions, or being transported in anambulance over rough roadways. Additionally, the optical couplerselectrically isolate the temperature, pressure and ECG sensors from therest of the system 100, which prevents a defibrillation signal fromdamaging the system 100. The power for the front end board 637 isisolated in a DC power supply located on the front end interface board636.

As shown in FIG. 22B, the electromechanical connectors, such as theconnector 704, include a portion, such as the portion 703, located onthe front end interface circuit board 636 and a portion, such as theportion 705, located on the front end circuit board 637. The portion 703includes an enlarged head 703 a mounted on a substantially straight andrigid stem 703 b. The head 703 includes an outwardly facingsubstantially flat surface 708. The portion 705 includes a substantiallystraight and rigid pin 705 including an end 705 a for contacting thesurface 708 and a spring-loaded end 705 b. Pin 705 can move axially inand out as shown by the directional arrow 721 while still maintainingelectrical contact with the surface 708 of the enlarged head 703 a. Thisfeature enables the single use module 634 to maintain electrical contactwith the multiple use module 650 even when experiencing mechanicaldisturbances associated with transport over rough terrain. An advantageof the flat surface 708 is that it allows for easy cleaning of theinterior surface of the multiple use module 650. According to theillustrative embodiment, the system 100 employs a connector for theelectrical interconnection between the single use disposable 634 andmultiple use 650 modules. An exemplary connector is part no. 101342 madeby Interconnect Devices. However, any suitable connector may be used.

Optical couplers, such as the optical couplers 684 and 687 of the frontend circuit board 637, are used and include corresponding counterparts,such as the optical couplers 683 and 685 of the front end interfacecircuit board 636. The optical transmitters and optical receiverportions of the optical couplers may be located on either circuit board636 or 637. For example, in the case of the ECG signal 379, the opticaltransmitter 684 is located on the circuit board 637 for receiving theelectrical signal 379 and optically coupling it to the optical receiver683 on the circuit board 636. In the case where the defibrillator signalis transmitted through the circuit boards 636 and 637 (rather thandirectly to the main board 718), the optical transmitter 685 on thecircuit board 636 optically couples the signal to the optical receiver687 on the circuit board 637.

As in the case of the electromechanical connectors employed, allowabletolerance in the optical alignment between the optical transmitters andcorresponding optical receivers enables the circuit boards 636 and 637to remain in optical communication even during transport over roughterrain. According to the illustrative embodiment, the system 100 usesoptical couplers made under part nos. SFH485P and/or SFH203PFA by Osram.However, any suitable coupler may be used.

The couplers and connectors facilitate the transmission of data withinthe system 100. The front-end interface circuit board 636 and thefront-end board 637 transmit data pertaining to the system 100 in apaced fashion. As shown in FIG. 22C, circuit board 636 transmits to thefront-end board 637 a clock signal that is synchronized to the clock onthe controller 150. The front-end circuit board 637 receives this clocksignal and uses it to synchronize its transmission of system data (suchas temperatures, pressures, ECG, r-wave detection, or other desiredinformation) with the clock cycle of the controller 150. This data isdigitized by a processor on the front-end circuit board 637 according tothe clock signal and a pre-set sequence of data type and source address(i.e. type and location of the sensor providing the data). The front-endinterface circuit board 636 receives the data from the front-end board637 and transmits the data set to the main board 618 for use by thecontroller 150 in evaluation, display, and system control, as describedabove with reference to FIGS. 11, 12 and 14. Additional optical couplerscan be added between the multiple use module and single use module fortransmission of control data from the multiple use module to the singleuse module, such data including heater control signals or pump controlsignals.

Having described the mechanical, electrical and optical interconnectionsbetween the single use module 634 and the multiple use module 650,additional components of the multiple use module 650 will now bediscussed with respect to FIGS. 23A-23D, followed by a description ofthe mechanical arrangement of the components of the single use module634 with respect to FIGS. 24A-28C. As shown in FIGS. 23A-23D, with thewalls of the housing 602 removed, in addition to those componentspreviously discussed, the multiple use module 650 includes an on-boardgas supply 172, located in the lower section 602 b of the housing 602.The gas supply 172 is depicted in FIGS. 23A-23D as a tank, positionedwithin the gas tank bay 630 by a support structure 712, which abuts thetank 172. Optionally, the gas supply 172 may be further secured withinthe gas tank bay 630 by a strap and buckle assembly 714 or othersuitable mechanism. With particular reference to FIG. 23B and asdescribed above with reference to FIG. 1, the gas supply 172 providesgas to the system 100 through the gas regulator 174 and the gas flowchamber 176. The gas pressure sensor 132 measures the gas pressure inthe gas supply 172, and the gas pressure gauge 178 provides a visualindication of the fullness of the gas supply 172. Additionally, anelectrical connection between the controller 150 and the gas flowchamber 176 enables the controller 150 to regulate automatically the gasflow into the oxygenator 114.

As shown most clearly in FIG. 23C, the battery bay 628 houses thebatteries 352 a-352 c. As noted above with reference to FIG. 14, alock-out mechanism is used to prevent more than one of the batteries 352a-352 c from being removed from the battery bay 628 at a given timewhile the system 100 is operating.

As discussed above, the system 100 includes a plurality ofinterconnected circuit boards for facilitating power distribution anddata transmission to, from and within the system 100. Particularly, asdiscussed above with reference to FIGS. 22A-22E and as shown in FIG.23C, the multiple use module 650 includes a front end interface circuitboard 636, which optically and electromechanically couples to the frontend circuit board 637 of the single use module 650. As also shown inFIG. 23C, the system 100 further includes a main board 718, a powercircuit board 720, and a battery interface board 711 located on themultiple use module 650. The main board 718 is configured to allow thesystem 100 to be fault tolerant, in that if a fault arises in theoperation of a given circuit board (as shown in FIG. 23D), the mainboard 718 saves pumping and heating parameters in non-volatile memory.When the system 100 reboots, it can re-capture and continue to performaccording to such parameters.

Referring to the conceptual drawing of FIG. 23D, cabling 731 bringspower (such as AC power 351) from a power source 350 to the powercircuit board 720 by way of connectors 744 and 730. The power supply 350converts the AC power to DC power and distributes the DC power asdescribed above with reference to the power subsystem of FIG. 14.Referring also to FIGS. 14 and 22A, the power circuit board 720 couplesDC power and a data signal 358 via respective cables 727 and 729 fromthe connectors 726 and 728 to corresponding connectors 713 and 715 onthe front end interface circuit board 636. Cable 729 carries both powerand a data signal to the front end interface board 636. Cable 727carries power to the heater 110 via the front-end interface board 636.The connectors 713 and 715 interfit with corresponding connectors 712and 714 (described above with respect to FIG. 22A) on the front endcircuit board 637 on the single use module 634 to provide power to thesingle use module 634.

As shown in FIG. 23D, the power circuit board 720 also provides DC power358 and a data signal from the connectors 732 and 734, respectively, onthe power circuit board 720 to corresponding connectors 736 and 738 onthe main circuit board 718 by way of the cables 733 and 735. Referringalso to FIGS. 14 and 19A, the cable 737 couples DC power 358 and a datasignal from a connector 740 on the main circuit board 718 to theoperator interface module 146 by way of a connector 742 on the operatorinterface module cradle 623. The power circuit board 720 also providesDC power 358 and a data signal from connectors 745 and 747 via cables741 and 743 to connectors 749 and 751 on a battery interface board 711.Cable 741 carries the DC power signal and cable 743 carries the datasignal. Battery interface board 711 distributes DC power and data tobatteries 352 a, 352 b and 352 c. Batteries 352 a, 352 b and 352 ccontain electronic circuits that allow them to communicate with eachother to monitor the respective charges, as described above in referenceto FIG. 14, so that the controller 150 can monitor and control thecharging and discharging of the batteries 352 a-352 c.

According to some illustrative embodiments, the controller 150 islocated on the main circuit board 718 and performs all control andprocessing required by the system 100. However, in other illustrativeembodiments, the controller 150 is distributed, locating some processingfunctionality on the front end interface circuit board 636, some on thepower circuit board 720, and/or some in the operator interface module146. Suitable cabling is provided between the various circuit boards,depending on whether and the degree to which the controller 150 isdistributed within the system 100.

As described above with reference to FIGS. 19A-19C and 23A-23C, thesystem 100 mechanically divides into the single use disposable module634 and the multiple use module 650. As also described above, accordingto the illustrative embodiment, the single use module 634 includes allor substantially all of the perfusion fluid 108 contactingelements/assemblies of the system 100, along with various peripheralcomponents, flow conduits, sensors and support electronics for operatingthe blood contacting components. As discussed above with reference toFIGS. 22A and 23D, according to the illustrative embodiment, the module634 does not include a processor, instead relying on the controller 150,which may, for example, be distributed between the front end interfacecircuit board 636, the power circuit board 720, the operator interfacemodule 146, and the main circuit board 718, for control. However, inother illustrative embodiments, the single use module 634 may includeits own controller/processor, for example, on the front end circuitboard 637.

Referring to FIGS. 24A-28C, the single use module 634 will next bedescribed in terms of the components included therein. After that,exemplary forward and retrograde flow modes are traced through thedescribed components.

Referring first to FIG. 24A, the disposable module 634 includes achassis 635 having upper 750 a and lower 750 b sections. The uppersection 750 a includes a platform 752 for supporting various components.The lower section 750 b supports the platform 752 and includesstructures for pivotably connecting with the multiple use module 650.More particularly, the lower chassis section 750 b includes the C-shapedmount 656 for rigidly mounting the perfusion fluid pump interfaceassembly 300, and the projection 662 for sliding into and snap fittingwith the slot 660 of FIG. 20B. The lower chassis section 750 b alsoprovides structures for mounting the oxygenator 114. As shown in FIGS.25A and 25C, the lower section 750 b further includes structures formounting the heater assembly 110. Additionally, the reservoir 160 mountsto the underside of the platform 725 and extends into the lower chassissection 750 b. Various sensors, such as the O₂ saturation and hematocritsensor 140 (shown in FIG. 24A and described in detail below withreference to FIGS. 28A-28C), the flow rate sensor 136 (shown in FIG.24A), the flow rate sensor 138 (shown in FIG. 25B), are located withinand/or mount to the lower chassis section 750 b. The flow pressurecompliance chamber 188 (shown in FIG. 25B) is also located in the lowerchassis section 750 b. As shown in FIG. 24D, the lower chassis section750 b also mounts the front end circuit board 637. Conduits located inthe lower chassis section 750 b are described in further detail belowwith reference to the normal and retrograde flow paths through thesingle use module 634.

Referring to FIGS. 24A-25C, and as mentioned above, the upper chassissection 750 a includes the platform 752. The platform 752 includeshandles 752 a and 752 b formed therein to assist in installing andremoving the single use module 634 from the multiple use module 650.Alternatively, such handles can be located on the platform 757 to allowfor easier accessibility during installation of the single use moduleinto the multiple use module. As shown most clearly in FIG. 24C, anangled platform 757 mounts onto the platform 752. The organ chamberassembly 104 mounts to the angled platform 757. According to theillustrative embodiment, with the single use module 634 installed withinthe multiple use module 650, the platform 757 is angled at about 10° toabout 80° relative to horizontal, to provide an optimal angle ofoperation for the heart 102 when placed within the organ chamberassembly 104. In some illustrative embodiments, the platform 757 isangled at about 20° to about 60°, or about 30° to about 50° relative tohorizontal. The flow mode selector valve 112, the flow rate sensor 134,and the perfusion fluid flow pressure compliance chambers 184 and 186also mount onto the angled platform 757.

Referring to FIG. 24E, several fluid ports mount to the platform 752.For example, a fluid sampling port 754 enables an operator to sample theflow into and/or out of the aorta 158 via the cannulation interface 162on the organ chamber assembly 104. A fluid sampling port 755 enables theoperator to sample the flow into the left atrium 152 via the interface170 on the organ chamber assembly 104. Additionally, a fluid port 758enables the operator to sample the coronary flow out of the pulmonaryartery 164 via the pulmonary artery interface 166 on the organ chamber104. According to the illustrative embodiment, the operator turns the arespective valve 754 a, 755 a or 758 a to obtain flow from the samplingports 754, 755 and 758. Flow from the particular port selected isprovided at a single common outlet 764. According to one feature, onlyflow from the left most port selected is provided at the outlet 764. Byway of example, if the operator opens both ports 755 and 758, only flowfrom port 755 is provided at the outlet 764. In this way, system 100reduces the likelihood of an operator mixing samples from multipleports.

The single use module 634 also includes a general injection port 762,operable with the valve 762 a, for enabling the operator to injectmedication into the perfusion fluid 108, for example, via the reservoir160. Both the sampling 764 and injection 762 ports mount to the platform752. Also located on the upper chassis section 750 a is an infusion port766, operable with the valve 766 a, for flowing the nutritional 116 andpreservative 118 fluids into the perfusion fluid 108. The upper chassissection 750 a also includes a tube 774 for loading the exsanguinatedblood from the donor into the reservoir 160. As shown in FIG. 24D, thesingle use module 634 also includes non-vented caps 776 for replacingvented caps on selected fluid ports that are used while running asterilization gas through the single use module 634 duringsterilization. Preferably, such sterilization takes place prior topackaging the single use module 634 for sale.

The upper chassis section 750 a also includes the flow clamp 190 forregulating back pressure applied to the left atrium 152 when the heart102 is cannulated and operating in normal flow mode in the organ chamberassembly 104. The upper chassis section 750 a further includes a tricklevalve 768. The trickle valve 768 may be opened and closed with thehandle 768 a to regulate a small fluid flow to the left atrium 152 tomoisten the left atrium 152 during retrograde flow mode. The upperchassis section 750 a also includes ports 770 for infusion of additionalsolutions and 772 for purging the oxygenator 114, operable withrespective valves 770 a and 772 a.

As shown most clearly in FIGS. 24A and 24D, the upper chassis section750 further includes the flow pressure probes 126, 128 and 130. Asdescribed above with reference to FIG. 1, the probe 126 measures thepressure of the perfusion fluid 108 flowing into/out of the aorta 158.The probe 128 measures the pressure of the perfusion fluid 108 flowinginto the left atrium 152 through the pulmonary vein 168. The probe 130measures the pressure of the perfusion fluid 108 flowing out of thepulmonary artery 164. Each probe includes a respective connector 126 a,128 a and 130 a (shown shortened for clarity) for coupling a respectivesignal 129, 131, and 133 to the front end circuit board 637.

Referring particularly to the single use module 654 cross-sectional sideview of FIG. 24C, the reservoir 160 includes several components. Morespecifically, the reservoir 160 includes four inlets: 782, 784, 786 and788. The inlet 782 transfers perfusion fluid 108 from the drain 201 ofthe organ chamber 194 into the reservoir 160. The inlet 784 receivesexsanguinated blood from the tube 774. The inlet 786 receives oxygenatedperfusion fluid 108 from the oxygenator 114, and the inlet 788 receivesperfusion fluid 108 out of the aorta 158 via the back pressure clamp190. The reservoir 160 also has an outlet 790, which provides theperfusion fluid to the one way inlet valve 191. The reservoir 160further includes a defoamer 778 and a filter 780. The defoamer 778removes bubbles out of the perfusion fluid 108 as it enters thereservoir 160. According to the illustrative embodiment, the defoamer ismade of porous polyurethane foam with an antifoam coating. The filter780 is a polyester felt, which filters debris, blood particles, emboli,and air bubbles out of the perfusion fluid as it enters the reservoir160.

As mentioned above in the summary, the O₂ saturation and hematocritsensor 140 employed in the single use module 634 includes importantadvantages over prior art approaches. FIGS. 28A-28C depict anillustrative embodiment of the O₂ saturation and hematocrit sensor 140of the invention. As shown in FIG. 28A, the sensor 140 includes anin-line cuvette shaped section of tube 812 connected to the conduit 798,which has at least one optically clear window through which an infraredsensor can provide infrared light. Exemplary sensors used in the in-linecuvette-shaped tube 812 are those made by Datamed, BL0P4. As shown inthe cross-sectional view of FIG. 28B, the cuvette 812 is a one-piecemolded part having connectors 801 a and 801 b. The connectors 801 a and801 b are configured to adjoin to connecting receptacles 803 a and 803b, respectively, of conduit ends 798 a and 798 b. This interconnectionbetween cuvette 812 and conduit ends 798 a and 798 b is configured so asto provide a substantially constant cross-sectional flow area insideconduit 798 and cuvette 812. The configuration thereby reduces, and insome embodiments substantially removes, discontinuities at theinterfaces 814 a and 814 b between the cuvette 812 and the conduit 798.Reduction/removal of the discontinuities enables the blood basedperfusion fluid 108 to flow through the cuvette with reduced lysing ofred blood cells and reduced turbulence, which enables a more accuratereading of perfusion fluid oxygen levels. This also reduces damage tothe perfusion fluid 108 by the system 100, which ultimately reducesdamage done to the heart 102 while being perfused by the system 100.

According to the illustrative embodiment, the cuvette 812 is formed froma light transmissive material, such as any suitable light transmissiveglass or polymer. As shown in FIG. 28A, the sensor 140 also includes anoptical transceiver 816 for directing light waves at perfusion fluid 108passing through the cuvette 812 and for measuring light transmissionand/or light reflectance to determine the amount of oxygen in theperfusion fluid 108. As illustrated in FIG. 28C, in some embodiments alight transmitter is located on one side of the cuvette 812 and adetector for measuring light transmission through the perfusion fluid108 is located on an opposite side of the cuvette 812. FIG. 28C depictsa top cross-sectional view of the cuvette 812 and the transceiver 816.The transceiver 816 fits around cuvette 812 such that transceiverinterior flat surfaces 811 and 813 mate against cuvette flat surfaces821 and 823, respectively, while the interior convex surface 815 oftransceiver 816 mates with the cuvette 812 convex surface 819. Inoperation, when uv light is transmitted from the transceiver 816, ittravels from flat surface 811 through the fluid 108 inside cuvette 812,and is received by flat surface 813. The flat surface 813 may beconfigured with a detector for measuring the light transmission throughthe fluid 108.

The fluid flow path through the single use module 634 in both normal andretrograde flow modes will now be described with reference to FIGS.24A-24D and FIG. 25A. As described above with reference to FIGS. 1-4,the system 100 can maintain the heart 102 in two modes of operation; anormal flow mode, shown in FIG. 3, and a retrograde flow mode shown inFIG. 4. As mentioned above with regard to FIG. 1, to change betweennormal and retrograde flow modes, the system 100 provides the flow modeselector valve 112, shown in detail in FIGS. 26A and 26B. To operate innormal flow mode, the operator sets the flow mode selector valve handle112 e to the position indicated in FIG. 24A. This has the effect ofaligning the flow paths through the selector valve 112 as shown in FIG.26A. Specifically, in normal flow mode, fluid can flow into port 112 b,through the flow channel 112 f and out the port 112 c. Additionally,fluid can flow into port 112 d, through the flow channel 112 g and outthe port 112 a. To operate in retrograde flow mode, the operator setsthe flow mode selector valve handle 112 e to the position indicated inFIG. 24B. This has the effect of aligning the flow paths through theselector valve 112 as shown in FIG. 26B. Specifically, in retrogradeflow mode, fluid can flow into port 112 b, through the flow channel 112h and out the port 112 d.

Referring to FIG. 24A, in normal flow mode, the reservoir 160 providesthe perfusion fluid 108 to the one way inlet valve 191 of the perfusionpump interface assembly 300. Referring to FIG. 25A, the perfusion pump106 pumps the perfusion fluid 108 out the outlet valve 310. Referring toFIG. 25C, the perfusion fluid 108 then flows through the conduit 792 andthe compliance chamber 188 and into the inlet 110 a of the heaterassembly 110. The heater assembly 110 heats the perfusion fluid 108 andthen flows it out the heater outlet 110 b. Referring to FIG. 24A, theheated perfusion fluid 108 flows from the heater outlet 110 b in thelower chassis section 750 b through the chassis plate 752 and into theport 112 b of the mode select valve 112 via the conduit 794. Referringalso to FIG. 24D, the perfusion fluid 108 flows out the mode valve port112 c, through the compliance chamber 186, the conduit 796, and thepressure sensor 128 into the pulmonary vein cannulation interface 170 onthe organ chamber assembly 104.

Referring to FIG. 24A, in normal flow mode, the heart 102 pumps theperfusion fluid 108 out the pulmonary artery 164 through the pulmonaryartery interface 166 and the pressure sensor 130. The conduit 796 thenflows the perfusion fluid 108 from the pulmonary artery interface 166through the plate 752 and through the O₂ saturation and hematocritsensor 140. Referring also to FIGS. 25A and 25C, the conduit 798 thenflows the perfusion fluid 108 from the sensor 140 through the flow-ratesensor 136 into the oxygenator 114. The conduit 800 flows the perfusionfluid 108 from the oxygenator 114 back into the reservoir 160 by way ofthe reservoir inlet 786.

Referring to FIGS. 24A, 24D and 24E, in normal flow mode, the heart 102also pumps the perfusion fluid 108 out of the aorta 158 through theaorta interface 162 and the pressure sensor 126. The conduit 802 flowsthe perfusion fluid 108 from the pressure sensor 126 through the flowrate sensor 134 and back into the port 112 d on the flow mode selectorvalve 112. A clamp 804 holds the conduit 802 in place. A conduit 806flows the perfusion fluid 108 out the port 112 a from the flow modeselector valve 112 through the compliance chamber 184 and the backpressure adjustment clamp 190. As mentioned above, the clamp 190 may beadjusted to restrict flow through the conduit 806 to adjust the backpressure seen by the aorta 158 during normal flow mode to morerealistically simulate normal physiologic conditions. The compliancechamber 184, which can expand and contract as perfusion fluid 108 ispumped into and out of it, interoperates with the clamp 190 to dampenflow pressure spikes to further improve simulation of near-normalphysiologic conditions. The after-load clamp 190 is configured toclosely emulate systemic vascular resistance of the human body whichaffects aortic pressure, left atrial pressure, and coronary flow. Aconduit 808 returns the perfusion fluid 108 into the reservoir 160 byway of the reservoir inlet 788.

In retrograde flow mode, the flow mode selector valve 112 is positionedas shown in FIG. 24B. Referring to FIG. 24B, the reservoir 160 providesthe perfusion fluid 108 to the inlet valve 191. As shown in FIG. 25A,the perfusion pump 106 pumps the perfusion fluid 108 out the outletvalve 310. As shown in FIG. 25C, the perfusion fluid 108 then flowsthrough the conduit 792 and the compliance chamber 188 and into theinlet 110 a of the heater assembly 110. The heater assembly 110 heatsthe perfusion fluid 108 and then flows it out the heater outlet 110 b.Referring to FIG. 24B, the heated perfusion fluid 108 flows from theheater outlet 110 b in the lower chassis section 750 b through thechassis plate 752 and into the input 112 b of the mode select valve 112via the conduit 794. Referring also to FIG. 24D, the perfusion fluid 108flows out the mode valve outlet 112 d, into the conduit 802, through theflow rate sensor 134, the pressure sensor 126 and into the aorta 158 viathe aorta interface 162. The perfusion fluid 108 then flows through thecoronary sinus 155 and the rest of the coronary vasculature.

Referring to FIG. 24B, in retrograde flow mode, the heart 102 pumps theperfusion fluid 108 out of the pulmonary artery 164 and through thepulmonary artery interface 166 and the pressure sensor 130. The conduit796 then flows the perfusion fluid from the pulmonary artery interface166 through the plate 752 and into the O₂ saturation and hematocritsensor 140. Referring also to FIGS. 25A and 25C, the conduit 798 thenflows the perfusion fluid 108 from the sensor 140 through the flow ratesensor 136 into the oxygenator 114. The conduit 800 flows the perfusionfluid 108 from the oxygenator 114 back into the reservoir 160 by way ofthe reservoir inlet 786. In retrograde flow mode, substantially noperfusion fluid is pumped into or out of the left atrium 152 via thepulmonary vein 168 and the pulmonary vein interface 170, with theexception of a small amount of perfusion fluid diverted by the tricklevalve 768 from the conduit 794 around the flow mode selector valve 112into the compliance chamber 186. As mentioned above, the trickle flowprovides sufficient perfusion fluid 108 to keep the left atrium 152moistened during retrograde flow.

As described above, the illustrative embodiment of the system 100 hasone or more sensors or probes for measuring fluid flow and pressure. Theprobes and/or sensors may be obtained from standard commercial sources.The flow rate sensors 134, 136 and 138 are conventional, ultrasonic flowsensors, such as those available from Transonic Systems Inc., Ithaca,N.Y. The fluid pressure probes 126, 128 and 130 may be conventional,strain gauge pressure sensors available from MSI or G.E. Thermometrics.Alternatively, a pre-calibrated pressure transducer chip can be embeddedinto organ chamber connectors and wired to a data collection site suchas the front end board 637.

Having described the electrical and mechanical components andfunctionality of illustrative embodiments of the system 100 and certainmodes of operation thereof, the system 100 will next be described withreference to the illustrative organ harvest and transplant procedures ofFIGS. 29A and 29B. More particularly, FIG. 29A is a flow diagram 900depicting exemplary methodologies for harvesting the donor heart 102 andcannulating it into the system 100 at a donor location. FIG. 29B depictsparticular points of care for handling the heart 102 in preparation forcannulation, and FIG. 30 is a flow diagram 902 of exemplarymethodologies for removing the donor organ 102 from the system 100 andtransplanting it into a patient at a recipient site.

As shown in FIG. 29A, the process of obtaining and preparing the heart102 for cannulation and transport begins by providing a suitable organdonor 904. The organ donor is brought to a donor location, whereupon theprocess of receiving and preparing the donor heart 102 for cannulationand transport proceeds down two intersecting pathways 906 and 908. Thepathway 906 principally involves preparing the donor heart 102 fortransplant, while the pathway 908 principally involves preparing thesystem 100 to receive the donor heart 102 and then transporting theheart 102 via system 100 to the recipient site.

With particular reference to FIG. 29A, the first pathway 906 includesexsanguinating the donor 910, arresting the donor heart 914, explantingthe heart 916, and preparing the heart 102 for cannulation 918 into thesystem 100. In particular, in the exsanguination step 910, the donor'sblood is removed and set aside so it can be used to perfuse the heart102 during preservation on the system 100. This step is performed byinserting a catheter into either the arterial or venous vasculature ofthe donor to allow the donor's blood to flow out of the donor and becollected into a blood collection bag. The donor's blood is allowed toflow out until the necessary amount of blood is collected, typically1.0-2.5 liters, whereupon the catheter is removed. The blood extractedthrough exsanguination is then filtered and added to a fluid reservoir160 of the system 100 in preparation for use with the system 100.Alternatively, the blood can be exsanguinated from the donor andfiltered for leukocytes and platelets in a single step that uses anapparatus having a filter integrated with the cannula and bloodcollection bag. An example of such a filter is a Pall BC2B filter. Afterthe donor's blood is exsanguinated, the donor heart 102 is injected instep 914 with a cardioplegic solution to temporarily halt beating inpreparation for harvesting the heart 102.

After the heart 102 is arrested, the heart 102 is explanted 916 from thedonor and prepared 918 for loading onto the system 100. In general, thesteps of explanting the heart 916 and preparing for loading 918 involvesevering the connections between the vasculature of the heart 102 andthe interior chest cavity of the donor, suturing various of the severedconnections, then lifting the heart 102 from the chest cavity.

More particularly, as shown in FIG. 29B, the right and left pulmonaryarteries 164 a and 164 b are severed, and the right pulmonary artery 164a is tied-off by a surgical thread 901 a or other suitable mechanism.The tying prevents fluid from flowing through the severed end 903 a ofthe left pulmonary artery 164 a. As described above with reference toFIGS. 24A-24B, the left pulmonary artery 164 b remains unsutured toallow it to be cannulated to the organ chamber assembly 104, therebyallowing perfusion fluid 108 to flow through the left pulmonary artery164 b, through the pulmonary artery cannulation interface 170, and backto the reservoir 160. The left pulmonary veins 168 b and 169 b and theright pulmonary veins 168 a and 169 a are also severed, and all except asingle pulmonary vein 169 b are tied off with surgical thread 901 b, 901c, and 901 d, respectively. This prevents fluid from flowing through thesevered ends 903 b and 903 c of the right pulmonary veins 168 a and 169a, or through the severed end 903 d of the left pulmonary vein 168 b,but allows the untied pulmonary vein to be cannulated to the organchamber assembly 104 through the pulmonary vein interface 170. Asdescribed above with reference to FIGS. 24A-24B, this arrangement allowsthe perfusion fluid 108 to flow through the right pulmonary artery 164b, through the pulmonary artery interface 166, and back to theoxygenator 114. Alternatively, blood can be expelled from the rightventricle via cannulating the pulmonary arterial trunk. The pulmonaryarterial trunk is not shown but includes the segment of pulmonary artery164 between the branches 164 a and 164 b of the pulmonary artery 164 andthe right ventricle 159. The superior vena cava 161 is also severed and,once the heart is connected to the system 100 and begins beating, istied with thread 901 e to prevent fluid from flowing through its end 903e. The inferior vena cava 163 is similarly severed and tied with thread901 f or oversewn to prevent fluid from flowing through its end 903 f.The aorta 158 is also severed (in the illustrated embodiment at a pointdownstream from the coronary sinus 155) but is not tied off, allowing itto be cannulated to the organ chamber assembly 104. In one embodiment,the aorta 158 is cannulated to an aortic connector, which can be easilyattached to the aorta interface 170.

With continued reference to the flow chart of FIG. 29A, after the heartvasculature is severed and appropriately tied, the heart 102 is thenloaded onto the system 100 by inserting it into the organ chamberassembly 104 and cannulating the aorta 158, left pulmonary artery 164 b,and a pulmonary vein 169 b to the appropriate points in the organchamber assembly 104.

Often, hearts obtained from donors who have also donated their lungs aremissing part or all of the left atrium 152. In this situation, the heart102 can still be instrumented and perfused in the retrograde mode bycannulating the aorta 158 and either the right pulmonary artery 164 a orpulmonary artery trunk (not shown, but described above), and allowingany remaining left atrium 152 portion to remain open during thepreservation period.

With continued reference to FIG. 29A, during the preparation of theheart via path 906, the system 100 is prepared through the steps of path908 so it is primed and waiting to receive the heart 102 for cannulationand transport as soon as the heart 102 is prepared. By quicklytransferring the heart 102 from the donor to the system 100, andsubsequently perfusing the heart 102 with the perfusion fluid 108, amedical operator can minimize the amount of time the heart 102 isdeprived of oxygen and other nutrients, and thus reduce ischemia andother ill effects that arise during current organ care techniques. Incertain embodiments, the amount of time between infusing the heart 102with cardioplegic solution and beginning flow of the perfusion fluid 108through the heart 102 via the system 100 is less than about 15 minutes.In other illustrative embodiments, the between-time is less than about ½hour, less than about 1 hour, less than about 2 hours, or even less thanabout 3 hours. Similarly, the time between transplanting the heart intoan organ care system 100 and bringing the heart 102 to a nearphysiological temperature (e.g., between about 34° C. and about 37° C.)occurs within a brief period of time so as to reduce ischemia within theheart tissues. In some illustrative embodiments, the period of time isless than about 5 minutes, while in other applications it may be lessthan about ½ hour, less than about 1 hour, less than about 2 hours, oreven less than about 3 hours. According to some illustrativeembodiments, the heart can be transferred directly from the donor to thesystem 100, without the use of cardioplegia, and in such applicationsthe time to beginning the flow of warm perfusion fluid 108 and/or timeto the heart reaching near physiologic temperature is similarly lessthan about 5 minutes, less than about ½ hour, less than about 1 hour,less than about 2 hours, or even less than about 3 hours. In oneimplementation, the donor heart is not arrested prior to removal fromthe donor, and is instrumented onto the system 100 while the heart 102is still beating.

As shown in FIG. 29A, the system 100 is prepared in pathway 908 througha series of steps, which include preparing the single use module 634(step 922), priming the system 100 with priming solution (step 924),filtering the blood from the donor and adding it to the system 100reservoir 160 (step 912), and connecting the heart 102 into the system100 (step 904). In particular, the step 922 of preparing the single usemodule 634 includes assembling the disposable single use module 634.Suitable assemblies are shown, for example, in FIGS. 24A-24D, FIGS.25A-25C, and FIG. 26. After the module 634 is assembled, or provided inthe appropriate assembly, it is then inserted into multiple use module650 through the process described above with reference to FIGS. 21A-21C.

In step 924, the loaded system 100 is primed with priming solution, asdescribed in more particular detail below with reference to Table 1.According to one feature, to aid in priming, the system 100 provides anorgan bypass conduit 810 shown installed into the organ chamber assembly104 in FIG. 27A. As depicted, the bypass conduit includes three segments810 a-810 c. Segment 810 a attaches to the pulmonary artery cannulationinterface 170. The segment 810 b attaches to the aorta cannulationinterface 810 b, and the segment 810 c attaches to the pulmonary veincannulation interface 166. Using the bypass conduit 810 soattached/cannulated into the organ chamber assembly 104, an operator cancause the system 100 to circulate the perfusion fluid 108 through all ofthe paths used during actual operation. This enables the system 100 tobe thoroughly tested and primed prior to cannulating the heart 102 intoplace.

In the next step 912, blood from the donor is filtered and added to thereservoir 160. The filtering process helps reduce the inflammatoryprocess through the complete or partial removal of leukocytes andplatelets. Additionally, the donor blood is mixed with one or morenutritional 116 and/or preservative 118 solutions to form the perfusionfluid 108. In step 926, the system 100 is primed with the perfusionfluid 108 by pumping it through the system 100 in the retrograde flowmode, as described above in reference to FIG. 24B, and with the bypassconduit 810 in place. As the perfusion fluid 108 circulates through thesystem 100 in priming step 926, it is warmed to the desired temperatureas it passes through heater assembly 110. The desired temperature rangeand heating applications are described above in reference to FIGS. 6Athrough 6E, and in respect to FIG. 13. In step 920, after the system 100is primed with the perfusion fluid 108, the bypass conduit 810 isremoved, and the heart 102 is instrumented, as described above and shownin FIG. 27B, onto the system 100.

After the heart 102 is instrumented onto the system 100, the pump 104 isactivated and the flow mode valve 112 is positioned in retrograde flowmode (described above with reference to FIGS. 1 and 4) to pump theperfusion fluid 108 in retrograde flow mode through the aorta into thevasculature of the heart 102. The pumping of the warm, oxygen andnutrient enriched perfusion fluid 108 through the heart 102 allows theheart 102 to function ex vivo in a near normal physiologic state. Inparticular, the warm perfusion fluid 108 warms the heart 102 as itperfuses through it, which may cause the heart 102 to resume beating inits natural fashion. In some instances, it is desirable to assist theheart 102 in resuming its beating, which may be done by providing handmassage or a defibrillation signal 143 (shown in FIG. 22E) to the heart102. This may be done as described above with reference to the organchamber assembly of FIGS. 5A-5F and operator interface 146 of FIGS.17A-17J.

After the heart is instrumented onto the system 100 at step 920,subsequent steps 928 and 930 allow the operator to test the heart 102and the system 100, and to evaluate their respective conditions.Illustratively, step 928 involves evaluating ECG signals 379 and 381from the sensors 142 and 144 (positioned as shown in FIG. 27A),respectively, as well as hematocrit 145 and oxygen saturation 141 levelsof the perfusion fluid 108 from the sensor 140. As further described inreference to FIG. 12 and FIGS. 17A-17I, the operator can also monitorthe fluid flows, pressures, and temperatures of the system 100 while theheart 102 is cannulated. As described above with reference to FIGS. 5Eand 5F, the testing step 928 may also include having the operatortouch/examine the heart 102 by lifting an outer lid 196 of the organchamber 104 and touching/examining the heart 102 indirectly through theflexible membrane 198 b. During the evaluation step 930, based on thedata and other information obtained during testing 928, the operatordetermines whether and how to adjust the system 100 properties (e.g.,fluid flows, pressures, and temperatures), and whether to provideadditional defibrillation, or other needed modes of treatment to theheart 102. The operator makes any such adjustments in step 932, thenrepeats steps 928 and 930 to re-test and re-evaluate the heart 102 andthe system 100. In certain embodiments, the operator may also opt toperform surgical, therapeutic or other procedures on the heart 102during the adjustment step 932. For example, the operator can conduct anevaluation of the physiological fitness of the heart, such as forexample, performing an ultrasound or other imaging test, performing anechocardiogram or diagnostic test on the heart, measuring arterial bloodgas levels and other evaluative tests.

In another application, during or after step 932, the system 100 allowsa medical operator to evaluate the organ for compatibility with anintended recipient after explantation but prior to implantation into thedonor. For example, the operator can perform a Human Leukocyte Antigen(HLA) matching test on the organ while the organ is cannulated to thesystem 100. Such tests may require 12 hours or longer and are performedto ensure compatibility of the organ with the intended recipient. Thepreservation of an organ using the system 100 described above may allowfor preservation times in excess of the time needed to complete an HLAmatch, potentially resulting in improved post-transplant outcomes. Inthe HLA matching test example, the HLA test can be performed on theheart while a preservation solution is pumping into the heart.

According to a further illustrative embodiment, after the heart isfunctioning as determined by the step 932, the operator can performsurgery on the heart or provide therapeutic or other treatment, such asimmunosuppressive treatments, chemotherapy, genetic testing andtherapies, or irradiation therapy. Because the system 100 allows theheart 102 to be perfused under near physiological temperature, fluidflow rate, and oxygen saturation levels, the heart 102 can be maintainedafter the adjustment step 932 for a long period of time (e.g., for aperiod of at least 3 days or more, greater than at least 1 week, atleast 3 weeks, or a month or more) to allow for repeated evaluation andtreatment.

According to the illustrative embodiment, the testing 928, evaluation930 and adjustment 932 steps may be conducted with the system 100operating in retrograde flow mode, or may be conducted with the system100 operating in normal flow mode. In normal flow mode, the operator cantest the function of the heart 102 under normal or near normalphysiologic blood flow conditions. Based on the evaluation 930, thesettings of the system 100 may be adjusted in step 932, if necessary, tomodify the flow, heating and/or other characteristics to stabilize theheart 102 in step 934 in preparation for transport to the recipient sitein step 936. After the heart 102 and the system 100 is tested andevaluated to ensure appropriate performance, the system 100 with theloaded heart 102 is transported to the recipient site at step 936.

Referring now to FIG. 30, the first phase 942 of the transplant processinvolves repeating the testing 928 and evaluation 930 steps undertakenjust prior to leaving the donor site 936. If the function andcharacteristics of the heart 102 are not acceptable, the system 100 canbe adjusted 942 as appropriate, for example, to provide appropriatefluid oxygenation or nutritional levels, or to increase or decrease theappropriate fluid temperature. As noted above, surgical and/or othertherapeutic/remedial procedures may be performed on the heart 102, alongwith the testing 928 and evaluation 930. According to the illustrativeembodiment, testing at the recipient site may be performed in retrogradeflow mode, normal flow mode, or a combination of both.

At step 946, after testing is complete, the system 100 is placed innormal/forward flow mode. In certain embodiments, this step 946 is notinitiated until the left atrium 152 and pulmonary vein 164 arecannulated, there is adequate operating volume in the system, the heartexhibits stable electrical activity, the ABG and electrolytes are withinacceptable ranges, SvO2 is >80%, and blood temperature is between about34° C. and about 36° C. The step 946 is may be accomplished by slowingand/or stopping the retrograde pumping of the system 100, thenrestarting the pumping in forward mode. In certain embodiments, prior torestarting in forward mode, the user opens the aortic sampling port 754a, releases the pressure control clamp 190 by turning itcounterclockwise, then increases the flow rate of pump 106 to about 1.0L/min, sets the flow control valve 112 to normal/forward flow, andincreases the flow rate of pump 106 to about 2.0 L/min to allow theblood 102 to displace air in the perfusate lines (e.g., 802) of thesystem 100 and pass through the left side of the heart 102 and down thereservoir return line 808. The user then closes the aortic sampling port754 a.

The flow rate of the perfusion fluid 108 emitted from the pump 106 isthen increased at step 950 to a level of the clinician's choosing(typically between about 1 L/min to about 5 L/min) to approximate thephysiologic flow rate provided by the heart 102 while functioning innormal beating mode. The heart 102 and the system 100 are again testedat step 952 in a similar fashion to that described above with respect tosteps 928 and 930. The clinician may also choose to perform any othertests or evaluations on the heart, for example echocardiogram,electrolyte measurements, cardiac enzyme measurements, metabolytemeasurements, intravascular ultrasound evaluation, pressure-volume loopevaluation, and Millar pressure evaluation.

In the third phase 946 at the recipient site, the heart 102 is preparedfor implantation into the recipient. This phase includes the step 956 ofpowering down the pump 106 to stop the flow of perfusion fluid 108.Next, in step 958, the heart 102 is arrested, for example by injectingit with cardioplegic solution in a similar fashion to what is done instep 914 at the donor site. In step 960, the heart 102 is de-cannulatedand removed from the organ chamber assembly 106. In step 962, the heart102 is transplanted into the recipient patient by first removing thesutures 901 a-901 f, then inserting the heart 102 into the recipient'schest cavity, and suturing the various heart vesicles (e.g., 158, 164 a,164 b, 168 a, 168 b, 169 a, 169 b, and 903 a-903 f) to their appropriatemating vesicles within the recipient.

While external devices and methods have been described to defibrillatethe heart, deliver pacing signals to the heart, and perform bloodchemistry analyses from samples taken from the perfusion fluid, it mayalso be beneficial to integrate these features into the portable system.Such features include defibrillation, pacing, diagnostic ECG sensing,and blood chemistry analyses.

As described above, the system 100 employs a priming solution, and alsoemploys a perfusion fluid 108 that combines a nutritional supplement 116solution and a preservative solution 118 with a blood product orsynthetic blood product to form the perfusion fluid 108. The priming,supplement 116, and preservative 118 solutions are described next.

According to certain embodiments, solutions with particular solutes andconcentrations are selected and proportioned to enable the organ tofunction at physiologic or near physiologic conditions. For example,such conditions include maintaining organ function at or near aphysiological temperature and/or preserving an organ in a state thatpermits normal cellular metabolism, such as protein synthesis. Exemplarysolutions for perfusing a heart are disclosed in U.S. ProvisionalApplication Ser. No. 60/793,472 and are incorporated by referenceherein.

Certain experimental data are available to describe certain embodimentsof solutions described herein and their use in heart perfusion and areset forth in FIGS. 31-33. FIG. 31 depicts a chart demonstratingelectrolyte stability for a heart under going perfusion in forward modeaccording to an embodiment of the system 100. In the embodimentassociated with FIG. 31, the organ is a heart 102 wherein perfusion isconducted in forward mode (as described above) by pumping perfusionfluid 108 containing solution 116/118 to the let atria 152 and out ofthe aorta 158. The rate of perfusion is approximately 30 mL/hr. As canbe seen from FIG. 31, the levels of various electrolytes: sodium,potassium, calcium, and chloride ions, as well as dissolved glucose,remain at stable levels throughout the course of perfusion, from beforethe organ is cannulated to the perfusion system 100 to six hours aftercannulation within the system 100.

FIG. 32 depicts a chart demonstrating electrolyte stability for an organunder going retrograde perfusion according to another embodiment of thesystem 100. In the embodiment associated with FIG. 32, the organ is aheart wherein perfusion occurs by pumping the perfusion fluid 108containing the solution 116/118 into the aorta 158 and through thecoronary sinus 155. The rate of perfusion is approximately 30 mL/hr. Ascan be seen from FIG. 32, the levels of various electrolytes: sodium,potassium, calcium, and chloride ions, as well as dissolved glucose,remain at stable levels throughout the course of perfusion, from beforethe organ is cannulated to the perfusion system 100 to six hours aftercannulation. FIG. 32 also demonstrates that the levels of theelectrolytes and glucose remain at levels similar to those for the baseline (BL) normal physiological state for the organ.

FIG. 33 depicts a chart demonstrating the arterial blood gas profile foran organ under going perfusion according to another embodiment of theinvention. As can be seen from FIG. 33, the levels of various bloodgasses: carbon dioxide and oxygen, and pH remain at stable levelsthroughout the six hour course of perfusion. FIG. 33 also demonstratesthat the levels of carbon dioxide, oxygen, and pH remain at levelssimilar to those for two base line (BL) measurements for the normalphysiological state for the organ. FIGS. 31-33 demonstrate the abilityof the present systems and methods to maintain an organ under stablephysiological or near physiological conditions.

The systems and methods described above for use in perfusing a heart exvivo may also be adapted for the maintenance of one or more lungs in anex vivo environment. In general, an exemplary system adapted for ex vivolung maintenance includes a perfusion circuit that can circulate warmblood or other perfusion fluid through the lungs, and one or more gassources for ventilating and supplying necessary oxygen, carbon dioxideand nitrogen to the lungs. An exemplary perfusion circuit includes apump to circulate the perfusion fluid and one or more cannulation orother interfaces for connecting the lungs within the perfusion circuit.Similar to the system 100, the lung maintenance system may also includeother features such as a gas exchange device (e.g., an oxygenator, or aventilator), a fluid heater to allow the user to control the temperatureof the perfusion fluid, and fluid pumping and heating process controlsystems. Nutritional sources may also be provided to replenishcarbohydrates, electrolytes and other components of the perfusion fluidthat are consumed during system operation.

An exemplary system for lung maintenance will next be described, alongwith a description of lung anatomical features that impact how the lungsare harvested and connected into the system. Exemplary techniques arethen described for maintaining lungs ex vivo and for evaluating lungs toascertain their functionality and suitability for transplantation. Anexemplary embodiment of the system and components thereof are thendescribed in further detail.

In certain embodiments, a lung maintenance system is configured in aportable module similar to the heart system described above, with bothsingle-use and multiple use components that allow for optimal costs ofproduction and system re-use. FIG. 34 depicts a schematic diagram of anexemplary portable lung care system 1000. The illustrated system 1000includes a disposable single use module 1002, similar to the single usemodule 634, and designed to inter-fit within the system 1000 forcontaining at least one lung during ex vivo maintenance and forregulating gas composition and flow of the perfusion fluid 108 (notshown) to and from the harvested organ. More particularly, as shown inFIGS. 41-43, the disposable module 1002 includes a lung chamber assembly1018, wherein at least one lung 1004 is instrumented via a pulmonaryartery interface 1022, a pulmonary vein interface 1026, and a trachealinterface 1024. The disposable module 1002 also includes a fluidreservoir 160 for containing the circulating perfusion fluid 108, aperfusion pump interface 300, a heater assembly 110, and a plurality offluid flow conduits and peripheral monitoring components. The single usemodule 1002 is described in further operational detail below withreference to FIGS. 34 and 41-43. The system 1000 also includes aperfusion fluid pump 106, a nutritional subsystem 115, a power subsystem148, an operator interface 146, a ventilation source 1003 (e.g., aventilator/respirator or a breathing circuit including a bag), acontroller 150 and a multiple use module 650 (not shown), similar tothose described above. In addition, the system 1000 includes one or moregas sources connected to the single use module 1002, each having anability to control pressure and flow rate of the gases. The exemplarysystem 1000 also includes a gas exchange device, which in certainembodiments is an oxygenator 114, for receiving and mixing gases fromthe one or more gas sources.

FIG. 35A depicts a pair of explanted lungs 1004 that can be connectedinto the system 1000 for extended ex vivo maintenance. The explantedlungs 1004 are excised from a donor along with a portion of the donor'spulmonary circuitry 1010, as illustrated in FIG. 36. In particular, theharvested lungs 1004 are excised from the donor by cutting across thedonor's left atrium 1009, which allows for the explantation of aplurality of pulmonary veins 1007 that connect respective lungs 1004 tothe piece of excised left atrial tissue, known as a left atrial cuff1008. The pulmonary veins 1007 are four in number, two from each lung,and include a right inferior vein 1007 a, a right superior vein 1007 b,a left inferior vein 1007 c and a left superior vein 1007 d. In analternative embodiment, multiple pieces of left atrial tissue areexcised from a donor, each connecting one or more pulmonary veins 1007to a single aggregation of the left atrial cuff. Excision is also madeat the donor's main pulmonary artery 1012, beginning at the base of thedonor's right ventricle 1014, to which both the donor's right pulmonaryartery 1005 a and left pulmonary artery 1005 b are confluently attached.Optionally, the explanted lungs 1004 also include the donor's trachea1006 through which air is transported into both of the lungs 1004.

FIG. 35B sets forth a close-up view of a single lung 1004 that isexplanted for use in the system 1000. The depicted left lung 1004 b isexcised from a donor by cutting across the donor's left atrium 1009, asdescribed above, which allows for the explanation of the left superior1007 c and inferior veins 1007 d that are joined at the excised leftatrial cuff 1008. The explanted lung 1004 b may also include the donor'sleft pulmonary artery 1005 b and, optionally, the donor's trachea 1006.

After explantation, lungs 1004 are placed in an ex vivo perfusion systemin which they are perfused during transport to a donor site, and inwhich they can be evaluated to ascertain their functionality andsuitability for transplantation.

More particularly, the system 1000 of FIG. 34 is adapted to maintain theexplanted lungs 1004 in two modes of operation—a maintenance mode and anevaluation mode. The maintenance mode is used by the system 1000 topreserve the lungs 1004 ex vivo for an extended period of time. Ingeneral, in the maintenance mode, the system 1000 circulates theperfusion fluid 108 into the lungs 1004 through the pulmonary arteryinterface 1022 and away from the lungs 1004 through the pulmonary veininterface 1026. The system 1000 also ventilates the lungs 1004 throughthe tracheal interface 1024 during perfusion. Ventilation occursmechanically by delivering a gas through the tracheal interface 1024 inbreaths that include periodic inspiration and expiration, in a mannerthat approximates the normal mechanical function of a lung in-vivo. Inan alternative embodiment, periodic inspiration and expiration isobtained in a protective ventilation fashion, whereby the breaths aretriggered by a critical opening pressure and a critical closing pressureto achieve a PEEP of about 8 to about 10 cmH₂O and a tidal volume ofabout 5 to about 7 ml/kg indicating the volume of gas flowing into thelungs with each breath. The breathing rate of the lung may be selectedby the operator. In certain implementations, the system 1000 provides 12or fewer breaths per minute; in certain implementations the systemprovides 6 breaths per minute. The number of breaths per minute isdetermined by the operator through the controller 150, which sends oneor more electrical signals to a valve in the tracheal conduit, whichopens and allows gas from the gas mixture to flow through the trachealinterface 1024 and into the lung. Ventilation can be done by lungventilators for example, VentiPAC Model 200D or PneuPac.

In addition, the system 1000 supplies a flow of a respiratory gas,having a pre-determined composition of gas components, to the lungs 1004for use in respiration by the lungs 1004 during perfusion. Upon reachinga steady state of the system 1000, the perfusion fluid 108 flowing intothe lungs 1004 includes a substantially constant composition of gascomponents, and the perfusion fluid 108 flowing away from the lungs 1004also includes a substantially constant composition of gas components. Asused herein, a substantially constant composition of a component in afluid is achieved at equilibrium, which occurs when the quantity of thecomponent in the fluid varies over time by an amount less than about 5%,less than about 3%, or less than about 1% at a given sampling locationwithin the system. In this respect, the perfusion fluid 108 used toperfuse the lungs 1004 includes equilibrium compositions of gascomponents. This mode of operation provides the amount of gas that needsto be supplied to the lungs 1004 for sustaining their viability duringextended periods of ex vivo maintenance and economizes thetransportation of the explanted lungs 1004 to the donor location. Asillustrated in FIGS. 37 and 38, the maintenance mode may be implementedusing two different approaches, both of which yield the steady statecondition in the perfusion fluid 108 as described above. In addition,FIG. 39 provides exemplary steady-state measurements of gas componentsin the perfusion fluid 108 obtained during one of the two maintenancemode approaches.

The maintenance mode is implemented in two exemplary approaches—atracheal oxygen delivery approach, and an isolated tracheal volumere-breathing approach. FIG. 37 depicts a flow diagram 1300 of the stepsinvolved in the tracheal oxygen delivery approach of the maintenancemode. At step 1302, the explanted lungs 1004 are instrumented within aperfusion circuit of the system 1000. At step 1304, the explanted lungs1004 are perfused by a perfusion fluid 108 that is oxygenated to adesired level prior to initiating the perfusion of the lungs 1004.Optionally, the perfusion fluid 108 may be brought to a high level ofoxygen prior to initiating the perfusion of the lungs 1004 so that aninitial high level of oxygen is delivered to the explanted lungs 1004.During perfusion of the lungs 1004, the oxygenated perfusion fluid 108flows into the explanted lungs 1004 via the pulmonary artery interface1022 and flows away from the lungs 1004 via the pulmonary vein interface1026 (step 1306). The explanted lungs 1004 are ventilated through thetracheal interface 1024 by a gas mixture that contains a pre-determinedcomposition of gas components for organ respiration (step 1308).

Ventilation is performed in this approach by flowing theventilation/respiratory gas into the tracheal interface 1024 in periodicbreaths containing a pre-determined volume and pressure of gas. Eachbreath includes a compression stage where the gas is delivered into thelung in a desired volume, followed by decompressing or relaxing of thelungs 1004 (and allowing the lungs 1004 to expel gas in an unaidedmanner) so that the lungs 1004 exhale the gas through the trachealinterface 1024 in a volume approximately equal to the compressionvolume. An outlet valve on the tracheal interface 1024 may be used toensure a minimum PEEP is maintained by preventing the pressure fallingbelow a user-determined value.

In certain embodiments, the respiratory gas mixture includes about 10%to about 20% oxygen, about 2% to about 8% carbon dioxide, and thebalance is nitrogen. In certain embodiments, the gas mixture includesabout 14% oxygen, about 5% carbon dioxide, and the balance is nitrogen.The oxygen component in the ventilation/respiratory gas provided throughthe tracheal interface 1024 enters alveoli of the lungs 1004 andexchanges with carbon dioxide from the perfusion fluid 108 flowing intothe lungs 1004. The perfusion fluid 108 that enters the lungs 1004 isoxygenated as a result of this exchange and then flows into thevasculature of the lung, where oxygen is consumed and carbon dioxideproduced. The lungs 1004 may consume oxygen in an amount less than theamount of oxygen provided in the tracheal breaths. The carbon dioxideproduced by the lungs 1004 passes into the perfusion fluid 108, theninto the alveoli and is excreted from the lungs 1004 via exhaled breathsthrough an outlet valve in the tracheal interface 1024. The outlet valveis provided across the tracheal interface 1024 to allow the exhaledbreaths to be expelled from the system 1000 and is described below withreference to FIG. 43.

In the tracheal oxygen delivery approach, the composition of theventilation/respiratory gas is pre-determined by the operator so as toestablish gas component equilibrium in the system. In other words,oxygen supplied to the lungs 1004 through the tracheal interface 1024 isconsumed in the lungs 1004 and resulting carbon dioxide is expelledthrough the tracheal interface 1024 without altering the gas compositionin the perfusion fluid 108 entering or exiting the lung. In equilibriumby this delivery approach, the perfusion fluid 108 flowing into thelungs 1004 and flowing away from the lungs 1004 have substantially thesame composition of oxygen and carbon dioxide, as indicated at step1310. Moreover, at step 1312, the lungs 1004 are perfused over anextended period of time while maintaining fluid and gas equilibrium inthe lung.

FIG. 38 depicts a flow diagram 1400 of the steps involved in the secondimplementation of the maintenance mode. Similar to the first mode, atstep 1402, the explanted lungs 1004 are instrumented within the lungcare system 1000. At step 1404, the instrumented lungs 1004 are perfusedwith a perfusion fluid 108 that flows into the lungs 1004 via thepulmonary artery interface 1022 and flows away from the lungs 1004 viathe pulmonary vein interface 1026. In addition, one or more respiratorygas mixtures, each containing a pre-determined composition of gascomponents, are supplied to the perfusion fluid 108 via a gas exchangedevice (e.g., oxygenator) 1042 of the system 1000 (step 1406). Morespecifically, a first gas source supplied to the oxygenator 1042includes a gas composition of about 11% to about 14% oxygen and about 3%to about 7% carbon dioxide, and the balance is nitrogen. In certaininstances, the first gas source includes about 12% oxygen and about 5%carbon dioxide, and the balance is nitrogen. Other gases may be used,for example nitric oxide (for endothelial protection and vasodilation)and carbon monoxide (to provide anti-apoptototic effects).

At step 1408, the lungs 1004 are also ventilated with an isolated gasvolume delivered through the tracheal interface 1024. The isolated gasvolume is provided in a configuration that prevents it fromcommunicating or otherwise interfacing with other fluids except in thelung alveoli. In this approach, the gas components in the isolated gasvolume are able to reach a substantially constant composition byexchanging with the gas components from the perfusion fluid 108 pumpedinto the lungs 1004 via the pulmonary artery interface 1022 (step 1408).This gas exchange takes place across the alveolar membrane of the lungs1004. Exhaled carbon dioxide component produced from the exchange isthen carried away from the lungs 1004 via the circulating perfusionfluid 108. This carbon dioxide component is substantially removed fromthe perfusion fluid 108 by the gas exchange device 1042.

Upon reaching equilibrium, as indicated in step 1410, oxygen and carbondioxide in the perfusion fluid 108 flowing into the lungs 1004 have asubstantially constant first composition, and oxygen and carbon dioxidein the perfusion fluid 108 flowing away from the lungs 1004 have asubstantially constant second composition. However, unlike in thetracheal oxygen delivery mode, in the isolated tracheal volume mode thefirst composition of oxygen and carbon dioxide components in theperfusion fluid 108 flowing into the lungs 1004 may differ from thesecond composition of the gas components in the perfusion fluid 108flowing away from the lungs 1004. In preferred embodiments of thisapproach, such first and second compositions differ by amountssubstantially equivalent to the quantity of oxygen consumed by the lungs1004 and the quantity of carbon dioxide produced by the lungs 1004during metabolism.

In certain embodiments, the oxygen composition in the perfusion fluid108 is maintained during perfusion at a steady-state partial pressure oroxygen saturation that is greater in the perfusion fluid 108 flowinginto the lungs 1004 than in the perfusion fluid 108 flowing away fromthe lungs 1004. In certain embodiments, the carbon dioxide component ismaintained during perfusion at a steady state partial pressure that islower in the perfusion fluid 108 flowing into the lungs 1004 than in theperfusion fluid 108 flowing out of the lungs 1004. This approach ofimplementing the maintenance mode is also referred to as an isolatedtracheal volume re-breathing approach, wherein oxygen supplied to theperfusion fluid 108 through the oxygenator 1042 is consumed in the lungs1004 and resulting carbon dioxide is carried away from the lungs 1004 bythe perfusion fluid 108 and removed through the oxygenator 1042.

Ventilation is performed in the second mode with breaths that occurapproximately as frequent as those provided in the first mode. However,ventilation in the second mode occurs by first compressing the isolatedgas volume, thereby flowing the gas from the isolated volume and intothe tracheal interface 1024, and then allowing the lungs to relax andexpirate gas, in an unaided manner, from the lung alveoli to fill theisolated volume.

In the maintenance mode, the system 1000 pumps the perfusion fluid 108to the lungs 1004 at a rate of about 500 to about 5000 ml/min. This modeof operation may help reduce damage to the lungs 1004 during extendedperiods of ex vivo maintenance. Thus, according to one feature of theinvention, the lungs 1004 are transported to a donor site in themaintenance mode. Additionally, the functional tests performed duringthe evaluation mode, described below, can also be conducted during themaintenance mode to evaluate various lung capabilities. In certaininstances, recruitment of the lungs 1004 may be performed in themaintenance mode. For example, a suction force may be applied to thelungs 1004 via the tracheal interface 1024 to clear the lungs 1004 offluid or alveoli debris. Collapsed alveoli in the lungs 1004 may beinflated by causing the lungs 1004 to inhale breaths that are ofvariable volume, such as sigh breathing which causes the lungs 1004 toinhale a first breath having a volume that is larger than the volumes ofat least two next breaths using, for example, a ventilator or abreathing circuit including a bag.

Having described the two different approaches of implementing amaintenance mode of operation with respect to FIGS. 37 and 38, exemplarymeasurements of gas components in the perfusion fluid 108 flowing intoand away from a pair of lungs 1004 equilibrium is described next for anisolated tracheal volume re-breathing approach. In particular, as shownin FIG. 39, data in column 4000 provides steady-state measurements ofgas components in the perfusion fluid 108 flowing into the explantedlungs 1004 through the pulmonary artery interface 1022. Data in column4002 provides steady-state measurements of gas components in theperfusion fluid 108 flowing away from the explanted lungs 1004 throughthe pulmonary vein interface 1026. The data in FIG. 39 was obtainedusing a blood gas analyzer, such as Radiometer ABL800 FLEX, to analyzesamples of perfusion fluid 108 taken during the isolated tracheal volumere-breathing approach. Briefly referring to the lung maintenance system1000 of FIGS. 41-43, a first sample of the perfusion fluid 108 was takenat port 1080 on the artieral fluid flow. This fluid sample was analyzedby the blood gas analyzer to generate the data in column 4000. For thesake of measurement accuracy, the radiometer was recalibrated afterperforming each analysis on a fluid sample. A second sample of theperfusion fluid 108 was taken at port 1082 and was analyzed by the bloodgas analyzer to generate the data in column 4002. The two sets ofmeasurements were spaced apart in time because of the recalibrationrequirement.

In general, during the maintenance mode, the perfusion fluid 108 flowinginto and away from the lungs 1004 are maintained at a relatively similargas component composition. For instance, the partial pressure 4000 a ofcarbon dioxide in the arterial fluid flow (43.8 mmHg) is only slightlylower than the partial pressure 4002 a of carbon dioxide in the venousfluid flow (44.6 mmHg), and the partial pressure 4000 b of oxygen in thearterial fluid flow (84.5 mmHg) is only slightly higher than the partialpressure 4002 b of oxygen in the venous fluid flow (83.9 mmHg). Thesedifferences in the partial pressures can be attributable to imprecisionin the measuring system, lung metabolism, or interactions with theoxygenator 1042.

In certain embodiments, the composition of gas components in theperfusion fluid 108 is chosen to provide steady-state partial pressuresof the gas components within the circulating fluid in a range between abody's physiologic arterial blood gas composition and physiologic venousblood gas composition. For example, as shown in FIG. 39, the compositionof the oxygen component in the perfusion fluid 108 is at a partialpressure that is greater than a composition of the oxygen component inphysiologic venous blood and less than a composition of the oxygencomponent in physiologic arterial blood. More specifically, this partialpressure of the oxygen component in the perfusion fluid 108 may bebetween about 75 mmHg to about 100 mmHg, between about 80 mmHg to about90 mmHg, or between about 83 mmHg to about 85 mmHg. In addition, asshown in FIG. 40, the composition of the carbon dioxide component in theperfusion fluid 108 is at a partial pressure that is less than acomposition of the carbon dioxide component in physiologic venous bloodand greater than a composition of the carbon dioxide component inphysiologic arterial blood. More specifically, this partial pressure ofthe carbon dioxide component in the perfusion fluid 108 may be betweenabout 40 mmHg to about 50 mmHg or between about 42 mmHg to about 48mmHg.

Having discussed the maintenance mode in detail with respect to FIGS.37-39, the evaluation mode is explained next. Techniques for evaluatingthe lungs 1004 to ascertain their functionality and suitability fortransplantation will also be described.

In particular, FIG. 40 provides a flow diagram 1200 illustrating thesteps involved in implementing the evaluation mode. As depicted, thesystem 1000 perfuses the explanted lungs 1004 with a perfusion fluid108. The perfusion fluid 108 is made to be similar in partial pressuresof blood gases to a body's physiologic venous blood. This venous gascomposition in the perfusion fluid 108 may be achieved by mixing one ormore gases, having a combined composition of carbon dioxide and low orno oxygen, with the perfusion fluid 108 (step 1204), until a desiredvenous composition is reached (1206), at which point the gases mayoptionally be stopped from being supplied to the perfusion fluid 108(step 1208). In one embodiment, the gases include about 5% carbondioxide and about 95% nitrogen. The perfusion fluid 108 is adapted toflow into the lungs 1004 through the pulmonary artery interface 1022 andflow away from the lungs 1004 through the pulmonary vein interface 1026.As indicated at step 1210, the explanted lungs 1004 may be ventilated byan oxygen-containing gas that is flowed into the tracheal interface 1024from a suitable ventilation source, such as from aventilator/respirator. This gas may comprise about 100% oxygen, aboutless than 100% oxygen, less than about 75% oxygen, less than about 50%oxygen or less than about 25% oxygen. In certain embodiments, this gasmay be the same composition as ambient air.

The evaluation mode is useful, for example, for performing tests toevaluate the gas-transfer capacity of the lungs 1004 by determining thepartial pressure or oxygen saturation of the perfusion fluid 108 bothbefore and after it flows through the lungs 1004. To perform this testin the evaluation mode, as shown at steps 1212 and 1214, the system 1000monitors the blood gas composition of the perfusion fluid 108 afterventilation begins by taking sample measurements of oxygen saturation orpartial pressure of oxygen in the perfusion fluid 108 flowing into thelungs 1004 via the pulmonary artery interface 1022 and flowing away fromthe lungs 1004 via the pulmonary vein interface 1026. The resultingpulmonary artery and pulmonary vein oxygen saturation or partialpressure oxygen measurements are then compared with each other toidentify a maximum difference that is representative of the gas-transfercapacity of the lungs 1004. In a second approach to evaluating thegas-transfer capacity of the lungs, the oxygen saturation or partialpressure of oxygen in the perfusion fluid flowing into the lungs 1004 istaken before ventilation begins. At a pre-determined time period afterventilation begins, another measurement of oxygen saturation or partialpressure of oxygen in the perfusion fluid flowing away from the lungs1004 is taken and is compared with the first measurement to evaluate thegas-transfer capacity of the lungs 1004. The operator determines whetherthis capacity is sufficient and decides to carry out the transplant, ornot. In addition, other functional tests on the lungs 1004 may beperformed, such as diagnostic bronchoscopy, visual evaluation andbiopsy, both prior and subsequent to transportation of the lungs 1004 toa donor location.

Exemplary functional tests performed on the lungs 1004 during theevaluation mode include tests that assess the gas exchange functionalityof the lungs 1004, which may be conducted using blood gas analysis offluid samples taken from both the arterial-side (e.g., through port1080) and venous-side (e.g., through port 1082) of fluid flow in theperfusion circuit. Tests can be conducted to assess pulmonarycirculation of the perfusion fluid 108 through the lungs. This mayinvolve the calculation of pulmonary vascular resistance (PVR) which isa measure of the ability of the lungs 1004 to resist fluid flow. Detailsregarding the PVR value calculation are provided below with respect toFIG. 52. In addition, alterations in the PVR value may be monitored inresponse to an infusion of nitric oxide into the perfusion fluid 108 todetect any reversibility of pulmonary hypertension. Pulmonaryangiography on the lungs 1004 may also be performed. In certainimplementations, assessment of the bronchial tree is conducted usingbronchoscopy along with other analysis applications such as inspectingthe airways, collecting bronchial washings for cytological ormicrobiological studies or obtaining multiple biopsies. In certainimplementations, image studies are performed on the lungs 1004 using,for example, x-rays, CTs, or nuclear studies such as perfusion orventilation scans. These imaging devices may be external to or onboardthe organ care system 1000. In certain instances, viability studies areconducted on parenchymal or bronchial tissue of the lungs 1004 usingtechniques such as biopsies or measurements of tissue levels of AMP, ADPand ATP. Additionally, assessments may be performed such as assessingthe severity of ischemia reperfusion injury in the instrumented lungs1004 by measuring levels of indicator agents, such as conjugated dienesor lactate, in the perfusion fluid 108. Moreover, a lung permeabilitytest may be perform on the explanted lungs to determine if the lungs areinjured or otherwise comprised. This test includes injecting an agent,such as a dye, into the perfusion fluid and, after a time period ofperfusion, visually inspecting the lungs. If the agent is visuallydetectable in the endo-bronchial tree of the lungs or in the alveoli,then the lungs are injured because they are permeable to the injectedsubstance. Further assessments include using biomarkers based onproteomic or genomic approaches to predict organ graft rejection ordevelopment of bronchiolitis obliterans syndrome (BOS) in a potentialorgan recipient. In certain instances, one or more of theabove-mentioned tests can be performed on the lungs 1004 during amaintenance mode of operation.

Having described the exemplary processes for implementing themaintenance mode and the evaluation mode, along with techniques forevaluating lungs 1004 to ascertain their functionality and suitabilityfor transplantation, features of the lung care system 1000 will bedescribed next in further detail with respect to these two modes ofoperation. In particular, instrumentation of the lungs 1004 within thesystem 1000 is described in further detail. Then a generalized approachfor operating the system is described, followed by a discussion ofspecific system features that are tailored to each mode of operation.

FIGS. 41-43 illustrate a pair of explanted lungs 1004, such as theexplanted lungs 1004 of FIG. 35 a, cannulated within an embodiment ofthe disposable single-use module 1002. In particular, the module 1002includes a lung chamber assembly 1018 that contains the explanted lungs1004 connected to the assembly 1018 from at least one of the pulmonaryartery interface 1022, the pulmonary vein interface 1026, and thetracheal interface 1024. The lungs 1004 may lay prone or supine in thelung chamber assembly 1018. With brief reference to FIG. 35A, thepulmonary artery interface 1022 includes a cannulation of the lungs 1004at or near the main pulmonary artery 1012. The tracheal interface 1024may include a cannulation of the lungs 1004 at or near the trachea 1006.In optional embodiments, where the trachea 1006 is not excised with thelungs 1004, the tracheal interface 1024 may include a conduit that isdirectly placed in a bronchial branch of each lung 1004, and the lungs1004 are vented by such conduit. The pulmonary vein interface 1026 mayinclude cannulation to the lungs 1004 at the excised left atrial cuff1008 where at least one of the pulmonary veins 1007 of the two lungs1004 is attached. However, in certain embodiments, the excised leftatrial cuff 1008 remains un-cannulated. Specific details regarding thepulmonary vein interface 1026 are discussed below in the context ofexemplary operational processes and with reference to FIGS. 48-51. Themodule 1002 also includes the reservoir 160 for holding the perfusionfluid 108 and an oxygenator 1042 that provides at least one appropriategas mixture to the perfusion fluid 108.

Referring again to FIGS. 34 and 41-43, in an illustrative embodiment ofa general operational process, the perfusion fluid 108 is prepared foruse within the module 1002 (and, ultimately, within the system 1000) bybeing loaded into the reservoir 160 via portal 774 and, optionally, istreated with therapeutics via portal 762. The loaded perfusion fluid 108is subsequently pumped from the reservoir 160 to the heater assembly 110and warmed to a near physiologic temperature. In this illustratedembodiment, this pumping action is provided by an alignment of the pumpinterface assembly 300 with the pump driver 334 of the multiple usemodule 650 which is described above with reference to FIG. 8C. The pumpinterface assembly 300 receives a pumping force from the pump driver 334and translates the pumping force to the perfusion fluid 108, therebycirculating the perfusion fluid 108 to the lung chamber assembly 1018.However, any fluid pump may be used to flow the perfusion fluid 108 inthe perfusion circuit. The heat assembly 110 includes temperaturesensors 120 and 122 and dual-sensor 124 that provide temperaturemeasurement of the perfusion fluid 108. A plurality of compliancechambers, such as compliance chambers 1086 a-c, may be included in thesystem 1000. They are essentially small inline fluid accumulators withflexible, resilient walls designed to simulate the human body's vascularcompliance by aiding the system 1000 to more accurately mimic blood flowin the human body. In particular, compliance chamber 1086 a is locatedat an outlet of the perfusion fluid pump 300, compliance chamber 1086 bis located at an outlet of the heater assembly 110, and compliancechamber 1086 c is located at an outlet of the oxygenator 1042. Any oneof these compliance chambers 1086 a-c may be used individually or aplurality of compliance chambers may be used in any combination.

The perfusion fluid 108 from the heater assembly 110 is then pumped tothe gas exchange device 1042. Depending on the flow mode selected aswell as the type of implementation chosen for executing the selectedflow mode, one or more mixing gases, each having a pre-determined gascomposition, may be automatically or manually supplied to the perfusionfluid 108 through the gas exchange device (e.g., an oxygenator) 1042. Incertain embodiments, the flow mode type selection is made using a modeselector switch 1020 located on the system 1000 between the gas suppliesand the oxygenator 1042. The mode selector switch 1020 may be operatedmanually as well as by the controller 150. In certain embodiments, theorder of the oxygenator 1042 and the heater assembly 110 along theillustrated perfusion circuit is switched.

Depending on the mode switch 1020 selected, the oxygenator 1042 receivesone or more mixing gases, from respective gas sources through gasregulators 174, 1030 a and 103 b and gas flow chambers 172, 1028 a and1028 b. The gas sources may be external to or onboard the system 1000.Gas pressure gauges, such as gauges 178, 1036 a and 1036 b, providevisual indication of the level of gas in the respective gas supplies172, 1028 a and 1028 b. Transducers 132, 1032 a and 1032 b providesimilar information to the controller 150. The controller is able toregulate automatically the gas flow from each gas source into theoxygenator 1042 in dependence, for example, on the perfusion fluidoxygen content measured at oxygenation/hematocrit sensor 1064, much likethe sensor 140 described above. This sensor also provides a signalindicative of a hematocrit measurement of the perfusion fluid 108.Subsequent to the mixing of the selected gases with the perfusion fluid108, the perfusion fluid 108 is pumped towards the lungs 1004 throughthe pulmonary artery interface 1022. In one exemplary embodiment, amixing gas supplied to the oxygenator 1042 from a gas flow chamber ispre-mixed to include a desired gas composition for infusion into theperfusion fluid 108. One or more additional gas sources each containing,for example, a high level of oxygen, carbon dioxide or hydrogen, may beadditionally supplied to the oxygenator 1042 from other gas flowchambers to modulate the composition of the mixing gas in the perfusionfluid 108. In another embodiment, gases having different compositionsare controllably released from the appropriate gas chambers to theoxygenator 1042 at rates and volumes that allow the desired gas mixturecomposition to be obtained in the perfusion fluid 108. However, forcertain perfusion modes, the oxygenator 1042 is not activated.

In certain practices, a flow rate sensor 1056, much like the flow ratesensor 134, is positioned along the arterial fluid flow from theoxygenator 1042 to the pulmonary artery interface 1022 to measure a flowrate of the fluid 108. A pressure sensor 1050, much like the pressuresensor 126 described above, is also positioned along the arterial fluidflow to measure the pressure of the perfusion fluid 108. This pressuresensor 1050 may be on an edge of the lung chamber assembly 1018 orinside of the assembly 1018 and as close as possible to a site ofpulmonary artery cannulation. In certain embodiments, a port 1080 isprovided for allowing an operator to extract samples of the perfusionfluid 108 along the arterial flow for further offline analysis.

The perfusion fluid 108 is then pumped into the lung chamber assembly1018 and the lungs 1004 cannulated therein via the pulmonary arteryinterface 1022. The pulmonary artery interface 1022 includes cannulationto the main pulmonary artery 1005 through an aperture 1040 a located onthe lung chamber assembly 1018. The lungs 1004 may be ventilated with agas mixture via the trachea interface 1024 that includes cannulation tothe trachea 1006 (or a substitute conduit not shown) via an aperture1040 b located on the lung chamber assembly 1018. Alternatively,cannulation may be made to a portion of a trachea 1006 intact on theexplanted lungs 1004. FIGS. 41-43 illustrate various approaches ofventilating the lungs 1004 through the tracheal interface 1024. Theseapproaches are mode-specific for the maintenance mode approachesdescribed above and as described below in further operational detail. Incertain embodiments, the controller 150 is able to regulate acomposition of gas components supplied to the lungs 1004 via thetracheal interface 1024 based on fractional inspired O₂ (FiO₂)concentration measurements and fractional expired CO₂ concentrationmeasurements obtained at FiO₂ meter 1030 and FiCO₂ meter 1031,respectively. A flow rate sensor 1067 may also be used to measure therate at which the lungs 1004 are ventilated via the tracheal interface1024. A pressure sensor 1068 may be used to measure the pressure of thegas supplied to the lungs 1004 via the tracheal interface 1024. Incertain embodiments, electrode sensors 1060 and 1062 are coupled to thelung chamber assembly 1018 to measure the weight and elasticity,respectively, of the explanted lungs 1004.

The perfusion fluid 108 is pumped out of the lung chamber assembly 1018via the pulmonary vein interface 1026 that includes, in certainembodiments, a cannulation to the pulmonary veins 1007 through anaperture 1040 c located on the lung chamber assembly 1018. In otherembodiments, the pulmonary veins 1007 remain un-cannulated. In general,the pulmonary vein interface 1026 establishes a return path of theperfusion fluid 108 from the pulmonary veins 1007 to the reservoir 160for continued circulation through the perfusion circuit. In addition, afluid passageway 1084 is provided that connects the lung chamberassembly to the reservoir 160. Along a path of fluid flow from thepulmonary vein interface 1026 to the reservoir 160, one or more sensorscan be positioned to provide measurements such as fluid flow rate viaflow rate sensor 1058, fluid pressure via pressure sensor 1052, andfluid oxygenation and hematocrit via sensor 1066. The pressure sensor1052 may be on an edge of the lung chamber assembly 1018 or inside ofthe assembly 1018 and as close as possible to the site of pulmonary veincannulation. In certain embodiments, a port 1082 is provided forallowing the operator to extract samples of the perfusion fluid 108along the venous flow. In certain embodiments, a flow clamp 1090, muchlike flow clamp 190 described above, is positioned along the path offluid flow from the pulmonary vein interface 1026 to the reservoir 160for regulating a back pressure applied to the pulmonary veins 1007 whenthe lungs 1004 are instrumented in the lung chamber assembly 1018.

Having described a generalized process for operating the system 1000,the system 1000 is next described in further detail with reference toindividual modes. These modes include the evaluation mode and themaintenance mode, the latter of which can be implemented using thetracheal oxygen delivery approach or the isolated tracheal volumere-breathing approach, as described above with reference to FIGS. 37 and38.

FIGS. 41 and 42 illustrate various embodiments of the single-used module1002 configured for use with the isolated tracheal re-breathingapproach. In particular, the first gas source, including a gascomposition of about 3% to about 7% carbon dioxide, about 11% to about14% oxygen, and the balance being nitrogen, is supplied to the gasexchange device (i.e., an oxygenator) 1042 for circulation through theperfusion system 1000. During perfusion, the perfusion fluid 108 ispumped into the lungs 1004 through the pulmonary artery interface 1022and pumped away from the lungs 1004 through the pulmonary vein interface1026. In addition, an isolated gas volume is delivered to the lungs 1004during perfusion via the tracheal interface 1024 to ventilate the lungs1004, as described above in FIG. 38. In one embodiment depicted in FIG.41, the isolated gas volume is provided by a flexible bag 1069 that maycontract and expand with each breath of the lungs 1004 during ex vivocare. In one embodiment depicted in FIG. 42, the constant gas volume isprovided by a hose 1050 connected to a gas source 1052 such as a gastank or a ventilator. The hose 1050 is appropriately configured to allowthe lungs 1004 to inspire a constant gas volume during perfusion. In yetanother embodiment, a specialized ventilator may be used to supply theconstant gas volume to the lungs 1004.

FIG. 43 illustrates an embodiment of the single-use module 1002configured for use with the tracheal oxygen delivery approach describedabove with reference to FIG. 37. The perfusion fluid 108 is oxygenatedto a desired gas component level prior to perfusing the lungs 1004. Thismay be achieved by circulating the perfusion fluid 108 through thesystem 1000 before lung instrumentation and supplying the fluid 108 withan appropriate gas mixture through, for example, the oxygenator 1042.After the perfusion fluid 108 reaches a desired gas component level, theoxygenator 1042 is deactivated to stop the delivery of respiratory gasto the perfusion fluid 108. The oxygenated perfusion fluid 108 issubsequently stored in the reservoir 160 before organ perfusion begins.

During perfusion, the perfusion fluid 108 is pumped from the reservoir160 to the heater assembly 110 and warmed to a near physiologictemperature before being supplied to the lungs 1004 in the lung chamberassembly via the pulmonary artery interface 1022. In the embodiment ofFIG. 43, the lungs 1004 are ventilated with a continuous supply of a gasmixture from an external gas source through an inlet valve 1060 of thetracheal interface 1024. As described above, in one implementation thegas mixture includes a composition of about 14% oxygen, about 5% carbondioxide, and the balance is nitrogen. The gas source may be a gaschamber 1062, such as gas chambers 172, 1028 a and 1028 b of FIG. 34,housed external to or onboard the system 1000. A gas pressure gauge1064, such as gauges 178, 1036 a and 1036 b of FIG. 34, provide visualindication of the pressure of gas in the chamber 1062. During perfusion,the oxygen component in the gas mixture inhaled by the lungs 1004through the inlet valve 1060 exchanges with the carbon dioxide componentin the perfusion fluid 108 across the alveoli of the lungs 1004, and thecarbon dioxide component is subsequently expelled from the alveoli in anexhaled breath via an outlet valve 1066 of the tracheal interface 1024.Both the inlet 1060 and the outlet 1066 valves are configured to preventsubstantial mixing of gas components between the gas mixture flowingthrough each valve. The perfusion fluid 108 flows out of the lungchamber assembly 1018 via the pulmonary vein interface 1026.

Having described the system 1000 in relation to the maintenance mode,the system 1000 is next discussed with respect to the evaluation mode.As mentioned above, the perfusion fluid 108 in the reservoir 160 isallowed to reach a pre-determined gas composition before tests areperformed on the lungs 1004 to evaluate, for example, their gas-transfercapability. The pre-determined gas composition may be, for example, aphysiologic venous blood-gas composition. This venous blood-gascomposition in the perfusion fluid 108 may be achieved by applying alow-oxygen or oxygen-free gas mixture to the perfusion fluid 108 throughthe oxygenator 1042 after the perfusion fluid 108 flows out of thereservoir 160. Exemplary low-oxygen or oxygen-free gas mixtures includea mixture having about 4% to about 11% carbon dioxide, about 0% to about8% oxygen, and the balance is nitrogen, a mixture having about 5% carbondioxide, about 0% oxygen and the balance is nitrogen, and a mixturehaving about 5% carbon dioxide, about 5% oxygen, and the balance isnitrogen. The resulting perfusion fluid 108 is optionally passed throughthe heater assembly 110, pumped into the lungs 1004 via the pulmonaryartery interface 1022, and flows away from the lungs 1004 via thepulmonary vein interface 1026, thereafter returning to the reservoir 160for subsequent return through the circuit. In this manner, the perfusionfluid 108 is circulated in the system 1000 until a venous blood gascomposition is reached in the perfusion fluid 108 flowing into andflowing away from the lungs 1004. After the perfusion fluid 108 reachesthe desired venous gas composition, the oxygenator 1042 may bedeactivated to stop the flow of low-oxygen or no-oxygen gas mixture tothe perfusion fluid 108. The lungs 1004 are then ventilated with anoxygen-containing gas from an external source via the tracheal interface1024. The gas-transfer capability of the lungs 1004 may thus bedetermined by monitoring the oxygen saturation or partial pressure ofoxygen on the venous and arterial flows of the perfusion fluid 108 afterventilation begins.

Thus far, an exemplary system 1000 for lung maintenance has beendescribed, along with a description of lung anatomical features thatimpact how the lungs 1004 are harvested and connected into the system1000. In addition, exemplary techniques have been described formaintaining lungs 1004 ex vivo during a maintenance mode of operation.Exemplary techniques have also been described for evaluating lungs 1004to ascertain their functionality and suitability for transplantationduring the evaluation mode. Moreover, exemplary features of the system1000 have been described in detail in relation to the various modes.Next, additional exemplary features of the system 1000 are discussed,including the lung chamber assembly 1018, the pulmonary vein interface1026, system controls, and data acquisition and display modules. Anexemplary transplantation procedure is then described, along with adescription of exemplary solutions that are used in the perfusioncircuit to care for the lungs 1004.

Various embodiments of the lung chamber assembly 1018 are described withreference to FIGS. 44-47. As depicted, the lung chamber assembly 1018may be rectangular in shape to house a pair of explanted lungs 1004.Alternatively, the lung chamber assembly 1018 may be triangular in shapeto accommodate a single explanted lung 1004. With brief reference toFIGS. 41-43, the lung chamber assembly 1018 includes apertures 1040a-1040 c adapted to receive the pulmonary artery interface 1022, thetrachea interface 1024 and the pulmonary vein interface 1026. Overall,the structure and material composition of the lung chamber assembly 1018closely resembles the organ chamber assembly 104 for the containment ofa heart described above and depicted in FIGS. 5A-5F, but expanded to asize sufficient to house a pair of lungs 1004. Particularly, theexplanted lungs 1004 may be contained in either a soft or hard shellcasing in the lung chamber assembly 1018. In certain embodiments, theassembly 1018 lies flat. In other embodiments, the assembly 1018 istilted at an adjustable angle such that the explanted lungs 1004 lie atthe same angle therein.

The shell casing of the lung chamber assembly 1018 may include asuspension mechanism to provide support and stability to the lungs 1004.Exemplary suspension mechanisms are depicted in FIGS. 44-47. In oneillustrative embodiment of the lung chamber assembly 1018 shown in FIG.44, a flexible membrane (e.g., a netting, fabric, cloth or othersuitably flexible material) is used to suspend the explanted lungs 1004in the lung chamber assembly 1018 so as to minimize contact between asurface of the lungs 1004 and one or more inner walls of the lungchamber assembly 1018. The membrane contacts a large portion of thesurface of the lung to support the lung's weight in a manner thatdistributes the weight across the membrane, thereby reducing thepressure on any particular region of the lungs 1004 and avoidingalveolar damage. The flexible membrane 1070 in the depicted embodimentis a netting structure. The netting structure 1070 may be meshed orporous and may substantially prevent alveoli in at least a portion ofthe lungs 1004 from collapsing while being held in the assembly 1018 forex vivo maintenance. In an alternative embodiment of the lung chamberassembly 1018 as illustrated in FIG. 45, the lungs 1004 may beadditionally or alternatively contained in a second netting 1072 thatsuspends the lungs 1004 from a top cover of or other structures withinthe assembly 1018. This second netting 1072 simulates the effects aribcage has on the lungs 1004 by preventing the lungs 1004 from overexpanding during respiration while maintaining their physiologic shape.The second netting 1072 may be constructed from the same material as thefirst netting 1070 or may be constructed from a substantially differentmaterial.

In certain embodiments, there is a support structure for the lungs thatsimulates the interior of the chest cavity, supporting the lungs onanterior and posterior sides, and helping the lungs to maintain theirphysiologic shape. For example, in an illustrative embodiment of thelung chamber assembly 1018 as shown in FIG. 46, a ribcage-shaped housing1074 is used to hold the explanted lungs 1004 in the lung chamberassembly 1018. This ribcage-shaped housing 1074, constructed from aflexible material, simulates the shape and movement of a real ribcage.In certain implementations as depicted in FIG. 47, a feature 1076similar to a body's diaphragm is coupled to the ribcage-shaped housing1074 (refer to the ribcage cut away in FIG. 47 for better view) byextending across a bottom portion of the housing 1074. This diaphragm1076 may also be constructed from a flexible material so that it maycontract and relax with each respiration of the lungs 1004.

Having described specific features of the lung chamber assembly 1018,exemplary features of the pulmonary vein interface 1026 are describednext with reference to FIGS. 48-51. More specifically, FIGS. 48-51illustrate various embodiments of connecting the pulmonary veins 1007 inthe system 1000 at the pulmonary vein interface 1026 as illustratedabove with reference to FIGS. 41-43. In certain embodiments the veins1007 are cannulated at the interface 1026. However, the pulmonary veins1007 may remain un-cannulated, such that fluid flowing away from thepulmonary veins 1007 freely drains into the lung chamber assembly 1018and returns to the reservoir 160 through passageway 1084, as depicted inthe system of FIGS. 41-43.

FIGS. 48Aa and 48B depict an exemplary apparatus for cannulation at thepulmonary vein interface 1026 of FIGS. 41-43. As illustrated, thecannulation device 1001 includes a funnel-shaped cannula 1100 havingproximal 1168 a and distal 1168 b ends and a connector device 1102having legs 1102 a and 1102 b. Using the connector device 1102, anoperator mates the cannula 1100 with the donor's excised left atrialcuff 1008 having all of the donor's pulmonary veins 1007 confluentlyattached. As the donor's pulmonary veins 1007 also attach to the donor'slungs 1004, the mating of the cannula 1100 with the cuff 1008 securessuch cuff 1008, veins 1007 and lungs 1004 within the system 1000.

As illustrated in FIG. 48B, the connector device 1102 includesconnection surfaces 1104 and 1112 that are used to form the matinginterface between the cuff 1008 and the cannula 1100. As shown, thesurfaces 1104 and 1112 are each configured as a ring with a hollowcenter and attached to respective legs 1102 a and 1102 b. The ring 1104is larger than a cross-section 1164 of the distal end 1168 b of thecannula 1100 but smaller than a cross-section 1162 of the proximal end1168 a of the cannula 1100 so that the ring 1104 can be secured behindthe funneled portion 1160 of the cannula 1100. In addition, the ring1112 is configured to be small enough in comparison to the size of theleft atrial cuff 1008 such that the cuff 1008 cannot easily be pulledout of the ring 1112 after the cuff 1008 has been pushed through thering 1112.

When operating the cannulation device 1001 according to the illustrativeembodiment, the ring 1104 is inserted on the distal end 1168 b of thecannula 1100 and slides through the length of the cannula 1100 until thering 1104 abuts and optionally tightly encircles a section of thecannula 1100. The excised left atrial cuff 1008 is then pushed throughthe ring 1112, leaving a portion 1170 of the cuff 1008 extending beyondthe perimeter of the ring 1112. An operator then compresses the handles1118 of the connector device 1102 until the left atrial cuff 1008 mateswith the funneled opening at the proximal end 1168 a of the cannula 1100so that locking mechanism 1103 a and 1103 b engage each other to keepthe connector device 1102 secured. The cannula 1100 is suitablyconfigured such that the funnel portion 1160 of the cannula 1100 is ableto receive and engage the left atrial cuff 1008. In certain embodiments,the cannula 1100 is malleable to allow it to be bent as needed to securethe lungs 1004 and inter-fit with the system 1000. A cannula 1100 ismalleable, in general, if it is able to bend but maintain a generallyconsistent cross-sectional diameter regardless of how severely it isbent. In certain embodiments, appropriately sized cannulas and connectordevices are provided to accommodate excised left atrial cuff of varioussizes.

After engaging the cuff 1008, the legs 1102 a and 1102 b are locked inplace by the locking mechanism 1103 a and 1103 b or other suitablemechanisms to hold the connector device 1102 at the compressed position.

FIGS. 49A and 49B depict another embodiment of the apparatus forcannulation at the pulmonary vein interface 1026. This apparatus is alsodesigned for use with a single piece of excised left atrial cuff havingall four of the donor's pulmonary veins 1007 confluently attached. Asshown in FIG. 49A, the connector device 1102 includes a first connectionsurface 1130 configured as a ring with a first inner peripheral surface1106 and a first outer O-ring seal 1108. The first inner peripheralsurface 1106 includes threads (not shown) that interlock with theoutwardly extending grooves 1110 projecting from the funnel-shapedcannula's outer peripheral surface 1111. Consequently, the cannula 1100is coaxially coupled to the ring 1130. The connector device 1102 alsoincludes a second connection surface 1112 configured as a ring with asecond inner peripheral surface 1114 and a second outer O-ring seal1116. In one embodiment as depicted in FIG. 49B, projections 1120 areregularly spaced around the circumference of the inner peripheralsurface 1114 to firmly engage a portion 1101 of the left atrial cuff1008 to the ring 1112 when the cuff 1008 is pushed through the ring1112. Other suitable mechanisms may be used to provide the sametissue-securing function. It is noted that the size of the second O-ringseal 1116 may be small enough in comparison to the size of the leftatrial cuff 1008 such that the portion 1101 of the cuff 1008 securelyrests within the O-ring seal 1116. In turn, the cannula 1100 and thefirst O-ring seal 1108 are accordingly configured such that when thefirst 1108 and second 1116 O-ring seals mate, a fluid tight seal isformed around the cannula 1100 and the portion 1101 of the left atrialcuff 1008. In certain embodiments, appropriately sized cannulas andconnector devices are provided to accommodate excised left atrial cuffof various sizes.

When operating the cannulation device 1001, the ring 1130 is screwed tothe outer peripheral surface 1111 of the cannula 1100 via the grooves1110 until tight. A portion 1101 of the excised left atrial cuff 1008 isthen pushed through the second inner peripheral surface 1114 of thesecond ring 1112 until the portion 1101 is securely fitted within theseal 1116. An operator then pushes together the handles 1118 of theconnector device 1102 until the first 1108 and second 1116 O-ring sealsmate to provide a seal around the cannula 1100 and the left atrial cuff1008. The legs 1102 a and 1102 b are then locked in place by a lockingpin (not shown) or other suitable mechanisms such as the lockingmechanism 1103 a and 1103 b of FIG. 48. In certain embodiments, to breakthe seal around the cannula 1100 and the left atrial cuff 1008, theoperator releases the locking pin (not shown) followed by pulling apartthe handles 1118 of the connector device 1102 until the first 1108 andsecond 116 O-ring seals separate.

FIGS. 50A and 50B depict yet another embodiment of the apparatus forcannulation at the pulmonary vein interface 1026. This apparatus isdesigned for use with the donor's left atrial cuff 1008 that is attachedto the four pulmonary veins 1007 of the donor. As illustrated 50B, thecannulation device 1001 includes a funnel-shaped cannula 1100 having aproximal end 1168 a, a connection surface 1800, a stopper 1804, and legs1102 a and 1102 b attached to the cannula 1100 and the connectionsurface 1800, respectively.

In certain embodiments, the proximal end 1168 a of the cannula 1100 andthe connection surface 1800 are configured to form a mating surface whenthe handles 1118 of the cannulation device 1001 are in a compressedposition and the stopper 1804 inter-fits within a center perforation1802 of the connection surface 1800. More specifically, the connectionsurface 1800 is configured as a square structure having a squareperforation 1802 etched through a center portion of the connectionsurface 1800. The stopper 1804 is adapted to inter-fit within the squareperforation 1802 such that the square perforation 1802 is divided intofour smaller square perforations 1802 a-d. A cross-section of theproximal end 1168 a of the cannula 1100 is also square in shape and issimilarly sized as a cross-section of the connection surface 1800. Inaddition, the size of each the smaller square perforations 1802 a-d issmall enough in comparison to the size of the left atrial cuff 1008 thatthe cuff 1008 cannot easily be pulled out of the perforations 1802 a-dafter the cuff 1008 has been pushed through the large perforation 1802and secured into place by the stopper 1804.

When operating the cannulation device 1001 according to the illustrativeembodiment, the excised left atrial cuff 1008 is pushed through thelarge center perforation 1802 of the connection surface 1800, leaving aportion of the cuff 1008 extending beyond a perimeter of the perforation1802. An operator then inter-fits the stopper 1804 into the centerperforation 1802 to secure the cuff 1800 to the connection surface 1800.The operator then compresses the handles 1118 of the cannulation device1001 until the left atrial cuff 1008 mates with the funneled opening atthe proximal end 1168 a of the cannula 1100. The cannula 1100 issuitably configured such that it is able to receive and engage all theleft atrial cuff 1008 secured to the connection surface 1800. In certainembodiments, the cannula 1100 is malleable to allow it to be bent asneeded to further secure the lungs 1004 and inter-fit with the system1000.

After engaging all the left atrial cuff 1008 to the cannula 1100, thelegs 1102 a and 1102 b are locked in place by a locking pin (not shown)or other suitable mechanisms to hold the connector device 1102 at thecompressed position.

Referring again to FIGS. 48-50B, in certain instances, a cross-sectionof a proximal opening 1168 a of a cannula 1100 may be larger in sizethan a cross-section of the left atrial cuff 1008 cannulated to thecannula 1100. This configuration allows a portion of the perfusion fluid108 flowing through the pulmonary veins 1007 to drain into the lungchamber assembly 1018 instead of flowing into the cannula 1100. Incertain instances, the mating interface between the cannula 1100 and theleft atrial cuff 1008 is configured to be semi-sealable so that at leasta portion of the perfusion fluid 108 flowing from the pulmonary veins1007 to the cannula 1100 is able to leak into the lung chamber assembly1018. In certain instances, the cannula 1100 is situated in the lungchamber assembly 1018 in a relatively upright position in relation theleft atrial cuff 1008 such that the perfusion fluid 108 flows in anupward direction from the left atrial cuff 1008 to the cannula 1100. Dueto the semi-sealable mating interface formed between the cannula 1100and the left atrial cuff 1008, a portion of the perfusion fluid 108 isadapted to seep out of the mating interface and drain into the lungchamber assembly 1018. A back pressure is subsequently created by theperfusion fluid 108 in the cannula 1100. In one example, this backpressure is created by a column of perfusion fluid 108 in the cannula1100 that is between about 1 cm to about 3 cm high.

FIG. 51A illustrates another embodiment of connection (e.g., bycannulation) at the pulmonary vein interface 1026. An excised leftatrial cuff 1008, having one or more pulmonary veins 1007 attachedthereto, is folded upon itself and sealed at a seam 1900 to form apocket interface 1902. In particular, the left atrial cuff 1008 isfolded in a manner such that the pulmonary veins 1007 are fluidlyconnected to a void interior region defined by the pocket interface1902. In addition, a proximal end 1168 a of a cannula 1100 is sealedwithin the pocket 1902 such that that the proximal opening 1168 a of thecannula 1100 is also fluidly connected to the void region of the pocketinterface 1902. This two-way connection between the pulmonary veins 1007and the cannula 1100 via the pocket interface 1902 is adapted to conductthe perfusion fluid 108 away from the lungs 1004 during perfusion. Thepocket interface 1902 may be surgically sewn or stapled together. Incertain embodiments, the pocket interface 1902 is relatively leak proofso that almost all of the fluid 108 flowing through the pulmonary veins1007 are conducted to the proximal opening 1168 a of the cannula 1100.In certain embodiments, the pocket interface 1902 is designed to allow acertain amount of the fluid 108 to drain into the lung chamber assembly1018 instead of flowing into the cannula 1100. This leaked-through fluid108 may be returned to the reservoir 160 via the passageway 1084 thatconnects the lung chamber assembly 1018 to the reservoir 160.

FIG. 51B illustrates yet another embodiment of connection (e.g., bycannulation) at the pulmonary vein interface 1026. An excised leftatrial cuff 1008 is lowered into a cup-shaped interface 4202 from a topopening 4210 (not shown) of the cup-shaped interface 4202 that islocated inside of the lung chamber assembly 1018. In an exemplaryembodiment, a size of the top opening 4210 is less than the size of theexplanted lungs 1004, but is small enough to allow the left atrial cuff1008 to be lowered comfortably into the interface 4202. The cup-shapedinterface 4202 also includes openings 4203 a-c situated at varyingheights along a sidewall of the interface 4202 and in fluidcommunication with a selector valve 4206 via conduits 4204 a-c,respectively. The selector valve 4206 is additionally coupled to anoutlet conduit 4208 that is adapted to conduct perfusion fluid 108 awayfrom the lung chamber assembly 1018 and into the reservoir 160. Incertain instances, the selector valve 4206 is manually orelectromechanically controlled by controller 150 and/or user interface146 to perform selective and controlled dispensing of the perfusionfluid 108 from the cup-shaped interface 4202 through a selected one ofthe openings 4203 a-c and into the outlet conduit 4208. Hence, theselector valve 4206 may be used to maintain a desired level of perfusionfluid 108 in the cup-shaped interface 4202. In operation, as perfusionfluid 108 exits from the pulmonary veins 1007 via the left atrial cuff1008, it collects into the cup-shaped interface 4204 until the height ofthe perfusion fluid 108 within the interface 4202 reaches one of theopenings 4203 a-c as set by the selector valve 4206. The fluid 108 thenexists the cup-shaped interface 4202 via the selected opening, flowsthrough the corresponding conduit, enters the selector valve 4206 andported away from the lung chamber assembly 1018 via the outlet conduit4208. Hence, the perfusion fluid 108 is able to fill the cup-shapedinterface 4202 to a height where the selected one of the openings 4203a-c is located in order to create a desired level of back pressure onthe pulmonary veins 1007.

Having described specific features of the lung chamber assembly 1018 andexemplary processes for cannulation at the pulmonary vein interface1026, details regarding the data acquisition and display modules of thesystem 1000 are described next.

In one aspect, the illustrative control system scheme depicted in theblock diagram of FIG. 11 is used for operating the system 1000 to carefor the explanted lungs 1004. Each subsystem depicted in the functionalblocks of FIG. 11 is particularly configured to maintain the lungs 1004in an optimally viable state at or near physiologic conditions. Morespecifically, the data acquisition subsystem 147, as illustrated in theblock diagram of FIG. 12, is modified to include sensors for obtaininginformation pertaining to the function of system 1000 and the lungs1004, and for communicating the information to the controller 150 forprocessing and use by the system 1000. As described above with referenceto FIGS. 41-43, the sensors used in the system 1000 include pressuresensors 1050, 1052 and 1068, flow rate sensors 1056, 1058 and 1067,oxygen/hematocrit sensors 1064 and 1066, FiO2 and FiCO2 concentrationmeters 1030 and 1031, weight sensor 1060, and elasticity sensor 1062.Some of the sensors utilized by the system 100 may also be utilized bythe system 1000. These sensors include the temperature sensors 120, 122and 124, the set of Hall sensors 388 and shaft encoder sensor 390 fromthe perfusion pump assembly 106, the battery sensors 352 a-352 c, theexternal power available sensor 354 and the operator interface modulebattery sensor 370.

The information obtained by the various sensors in the data acquisitionsubsystem 147 is transmitted to the controller 150 and displayed via theoperator interface subsystem 146. The operator interface subsystem 146includes a display screen 3100, as depicted in FIG. 52, that shows anumber of numerical and graphical indications pertaining to the care oflungs 1004. In particular, the display screen 3100 includes a displayarea 3140 showing a waveform depiction 3148 of the pulmonary arterialpressure (PAP). The display area 3140 also includes a numerical display3152 of a PAP reading, as measured by the pressure sensor 1050. Displayarea 3142 of the display screen 3100 shows a waveform depiction 3150 ofthe left atrial or pulmonary venous pressure (LAP) and a reading 3154 ofthe LAP, as measured by the pressure sensor 1052. Display area 3144includes a waveform depiction 3156 of the respiration-ventilationpressure through the tracheal interface 1024 (RESP) and a reading 3158of the RESP, as measured by the pressure sensor 1068. In certainembodiments, the displayed PAP, LAP and RESP values are instantaneousreadings. In certain embodiments, the PAP and LAP values are displayedas an average, a mean or a minimum of instantaneous readings collectedover a time period that is less than 30 seconds, less than 20 seconds,or less than 10 seconds. In certain embodiments, the RESP value isdisplayed as an average or a minimum of instantaneous readings collectedover a time period that is less than 30 seconds, less than 20 seconds,or less than 10 seconds. In addition, the waveforms 3148, 3150, and 3156are displayed on a real-time basis or a periodic basis with each batchof data collected.

The display screen 3100 further includes a number of additional displayareas 3102, 3104, 3106, 3108, 3110, 3112, 3114, and 3116. The displayarea 3102 shows a numerical reading 3160 of the pulmonary flow (PF) ofthe perfusion fluid 108 into the lungs 1004 via the pulmonary arteryinterface 1022, as measured by the flow rate sensor 1056. The displayarea 3104 shows a numerical value 3162 representative of pulmonaryvascular resistance (PVR). The PVR value 3162 indicates the amount ofresistance the lungs 1004 exert to a flow of the perfusion fluid 108 andis calculated by subtracting a LAP value, such as the LAP reading 3154,from a PAP value, such as the PAP reading 3152, divided by a PF value,such as the PF reading 3160 and applying a unit conversion factor. Ingeneral, a lower PVR value 3162 is preferable because it indicates aless restricted flow of the perfusion fluid 108 through the vasculatureof the lungs 1004. In certain embodiments, favorable values of the PVRis in a range between about 200 dynes to about 400 dynes. The displayarea 3106 shows the venous oxygen saturation (SvO₂) 3164 of theperfusion fluid 108, as measured from the oxygen/hemacorit sensor 1066.Similarly, the display area 3108 shows the arterial oxygen saturation(SaO₂) 3166 of the perfusion fluid 108, as measured from theoxygen/hemacorit sensor 1064. In certain embodiments, the display areas3106 and 3108 additionally include a SvO₂ alarm and a Sa O₂ alarm,respectively, for signaling the operator if each oxygen saturation valuefalls below an operator preset threshold. Such alarm may be implementedfor any parameter measured, calculated or displayed. The display area3110 includes a numerical reading 3168 of the hematocrit (HCT) of theperfusion fluid 108 and, optionally, an HCT alarm indicator forsignaling the operator if the HCT 3168 falls below an operator presetthreshold. The display area 3112 indicates the temperature (Temp) 3170of the perfusion fluid 108 as it flows away from the heater assembly110. The display area 3112 may also include a Temp alarm indicator whichsignals in response to the Temp 3170 being outside of an operator presetrange. A temperature set point 3172 selected by the operator is alsoshown in the display area 3112. The display area 3114 shows a numericalreading 3174 of the ventilation rate measured as breaths per minute(BPM) of a gas delivered to the lungs 1004 via the tracheal interface1024. A BPM reading may be ascertained from a flow sensor, communicatedfrom a respirator, or obtained from a pressure sensor, such as pressuresensor 1068. The BPM value 3174 may be measured at the flow rate sensor1067. In addition, the display area 3114 includes a BPM alarm indicator3176 signaling if the BPM value 3174 is outside of an operator presetrange. The display area 3116 includes a numerical display 3178 of tidalvolume (TDLV) of a gas flow into the lungs 1004 with each breath of thelungs 1004 and a TDLV alarm indicator 3180 signaling if the TDLV value3178 is outside of an operator preset range.

The display screen 3100 further includes a circulatory pump indicator3118 showing a status of the system's circulatory pump, a perfusionfluid warmer indicator 3120 showing a status of the perfusion fluidheater assembly 110, and an SD card indicator 3124 showing whether an SDcard is used to store data collected during organ perfusion. A displayarea 3126 is provided that includes a gas tank image 3182 graphicallyindicating a remaining gas volume in a gas supply connected to thesystem 1000. The display area 3126 also includes one or more numericaldisplays 3184 indicating a flow rate of the gas in the gas supply alongwith the time remaining for which the gas is delivered to the lungs 1004during perfusion. This remaining time may be calculated based on theremaining gas volume and the gas flow rate. Display area 3122 shows anorgan type indicator 3186 that indicates which organ is being perfusedand an organ mode indicator 3188 that indicates what mode of operationis being used to perfuse the organ. For example, an “R” is used toindicate a maintenance mode of operation. Display area 3190 shows agraphical representation 3128 of the degree to which each of thebatteries 352 a-352 c of the multi-use module 650 is charged. Batterystatus symbol 3130 indicates that the batteries 352 a-352 c, whosestatus are represented by graphical representation 3128, are used topower the multi-use module 650. The display area 3146 may also provide anumerical indication of the amount of time remaining for which thebatteries 352 a-352 c can continue to run the system 1000 in the currentmode of operation. Display area 3192 shows a graphical representation3132 of the degree to which the user interface battery 368 is chargedand a numerical indication 3194 of the amount of time remaining forwhich the user interface battery 368 can continue to run the userinterface module 146. A battery status symbol 3134 indicates that theuser interface battery 368, whose status is represented by the graphicalrepresentation 3132, is used to power the user interface 146. Displayarea 3136 identifies whether the operator interface module 146 isoperating in a wireless fashion 3196, along with a graphicalrepresentation 3198 of the quality of the wireless connection betweenthe operator interface module 146 and the remainder of the system 1000.The display screen 3100 also includes an alarm image 3101 indicatingwhether any parameter of the system 1000 is outside of a preset operatorthreshold for that parameter (the alarm 3101 is shown as “off” in FIG.52) or communicating a system-related alarm message. The display screen3100 further includes a display area 3146 showing a time and date ofsystem operation and a display area 3138 showing the amount of timeelapsed since perfusion begins.

In other embodiments, the display screen 3100 also shows FiO₂ and FiCO₂concentrations, which are fractional concentrations of oxygen and carbondioxide, respectively, measured via sensors 1030 and 1031 across thetrachea interface 1024. Moreover, the display screen 3100 canadditionally show readings of weight and elasticity of the lungs 1004,PH of the perfusion fluid 108 circulating through the lungs 1004,partial pressures of gas components in the perfusion fluid, and positiveend expiratory pressures (PEEP) of the lungs 1004 which indicate thepressure in the lungs 1004 at the end of an exhaled breath.

Having described specific features of the lung chamber assembly 1018,exemplary processes for cannulation at the pulmonary vein interface1026, and the data acquisition and display modules of the system 1000,an exemplary lung transplantation procedure is described next withreference to FIGS. 53 and 54.

The process of obtaining and preparing the lungs 1004 for cannulationand transport as shown in FIG. 53 is similar to the steps shown in FIG.29A for the care of a heart. This process begins by providing a suitableorgan donor at step 2000. The organ donor is brought to a donorlocation, whereupon the process of receiving and preparing the donorlungs 1004 for cannulation and transport proceeds down two intersectingpathways. The pathways principally involve preparing the system 1000 toreceive the donor lungs 1004 and then transport the lungs 1004 viasystem 1000 to a recipient site. In particular, pathway 2002 includesexsanguinating the donor, arresting the donor's heart, and preparing thelungs 1004 for cannulation into the system 1000. In particular, in theexsanguination step 2006, the donor's blood is removed and set aside soit can be used to perfuse the lungs 1004 during their maintenance on thesystem 1000. Steps involved in removing blood from the exanguinateddonor are described above with respect to FIG. 29A. After the donor'sblood is exanguinated, the donor heart is injected in step 2008 with acardioplegic solution to temporarily halt its beating in preparation forharvesting the lungs 1004.

After the donor's heart is arrested, a pneumoplegia solution isadministered to the lungs at step 2009 before the lungs 1004 areexplanted from the donor at step 2010 and prepared for loading onto thesystem 1000 at step 2012. Processes involved in explanting a single lungor a pair of lungs 1004 are explained above with respect to FIGS. 35 and36.

With continued reference to FIG. 53, after the lungs 1004 are explantedfrom the donor's body, they are instrumented onto the system 1000 atstep 2021 by insertion into the lung chamber assembly 1018 andcannulation at the appropriate interfaces as described above withrespect to FIGS. 34 and 48-51.

According to other illustrative embodiments, the lungs 1004 can betransferred directly from the donor to the system 1000 without the useof cardioplegia. In one particular implementation, the donor's lungs1004 are removed without the donor's heart being arrested and aresubsequently instrumented into the system 1000 for maintenance.

During the preparation of the lungs 1004 via path 2002, the system 1000is prepared through the steps of path 2004 so it is primed and waitingto receive the lungs 1004 for cannulation and transport as soon as thelungs 1004 are prepared. In particular, the system 1000 is prepared inpathway 2004 through a series of steps including providing the singleuse module 1002 (step 2014), priming the system 1000 with a primarysolution (step 2016), filtering the blood from the donor and adding itto the reservoir 160 (step 2018), and priming the system 1000 with amixture of the blood and the perfusion fluid 108 (step 2020). In certainembodiments, the perfusion fluid 108 includes whole blood. In certainembodiments, the perfusion fluid 108 is partially or completely depletedof leukocytes. In certain embodiments, the perfusion fluid 108 ispartially or completely depleted of platelets. The priming,supplemental, and preservative solutions utilized by the organ caresystem 100 for the maintenance of a heart may also be used in the system1000. In certain embodiments, the solutions used with the system 100 areused, but new additives including prostaglandin E, Prostacycline,dextran, isuprel, flolan and nitric oxide donors are added whileepinephrine is removed. The additives may be generally selected fromantimicrobials, vasodilators, and anti-inflammatory drugs. The additivesmay be delivered to the system 1000 via ports 762 and 774 coupled to thereservoir 160 or via the tracheal interface 1024 through a nebulizer ora bronchoscope. The various solutions utilized by the organ care system1000 will be described below in further detail.

At step 2022, the system 1000 is selected to operate in the maintenancemode. Different approaches of implementing the maintenance mode aredescribed above with reference to FIGS. 37 and 38. In general, theexplanted lungs 1004 are connected into the system 1000. The perfusionfluid 108 is pumped into the lungs 1004 through the pulmonary arteryinterface 1022 and pumped away from the lungs 1004 through the pulmonaryvein interface 1026. A supply of gas, either as an isolated volume or acontinuous flow, is provided to the lungs 1004 via the trachealinterface 1024. A flow of a respiratory gas, having a pre-determinedcomposition of gas components, is also provided to the lungs 1004 foruse in respiration by the lungs 1004 during perfusion. In addition, at asteady-state of the system 1000, a composition of gas components in theperfusion fluid 108 flowing into the lungs 1004 includes a substantiallyconstant composition of components, and the perfusion fluid 108 flowingaway from the lungs 1004 also includes a substantially constantcomposition of components. Moreover, at step 2024, the instrumentedlungs 1004 may be monitored and assessed using a plurality of monitoringcomponents coupled to the system 1000.

Based on the monitored parameters, in some instances, it is desirable toprovide recruitment to the lungs 1004 during the maintenance mode (step2026). For example, the lungs 1004 may be treated with antimicrobials orsuctioned to remove fluid and alveoli debris in the trachea 1006.Collapsed alveoli in the lungs 1004 may be inflated using sigh breathingby causing the lungs 1004 to inhale breaths that are of variable volume,such as causing the lungs 1004 to inhale a first breath having a volumethat is larger than the volumes of at least two next breaths. In someinstances, an operator may perform surgery on the lungs 1004 or providetherapeutic or other treatment, such as immunosuppressive treatments,chemotherapy, genetic testing or irradiation therapy. Additionalassessments of the lungs 1004 are described above with respect to FIGS.37-40.

FIG. 54 provides an exemplary process for conducting additional tests onthe lungs 1004 while the system 1000 is at the recipient site (step3000). In particular, at step 3002, the system 1000 is set to operate inthe evaluation mode in order to provide a perfusion condition that issuitable for the evaluation of the lungs 1004 to determine theirgas-transfer capacity. Additional recruitment can be performed duringthe evaluation mode at step 3003 based on assessment of the lungs 1004performed at step 3005. Steps involved in implementing the evaluationmode are described above in detail with reference to FIG. 39. Aftertesting is complete at the recipient site, the lungs 1004 are preparedfor implantation into the recipient. This includes configuring thesystem 1000 for lung removal by powering down the pump 106 to stop theflow of perfusion fluid 108 (step 3004) and, optionally, administering apneumoplegia solution to the lungs 1004. Next, in step 3008, the lungs1004 are de-cannulated and removed from the lung chamber assembly 1018.In step 3018, the lungs 1004 are transplanted into the recipient patientby inserting them into the recipient's chest cavity and suturing thevarious pulmonary connections to their appropriate mating connectionswithin the recipient. In certain embodiments, a portion of therecipient's left atrium may be excised and replaced with one or more ofthe donor's left atrial cuff 1008 to which the donor's pulmonary veinsare attached.

As described above, the system 1000 employs a priming solution, and alsoa perfusion fluid 108 that combines a nutritional supplement 116solution and a preservative solution 118 with a blood product orsynthetic blood product to form the perfusion fluid 108. The priming,supplement 116, and preservative 118 solutions are described next.

According to certain embodiments, solutions with particular solutes andconcentrations are selected and proportioned for the perfusion fluid 108to enable the lungs 1004 to function at physiologic or near physiologicconditions. For example, such conditions include maintaining lungfunction at or near a physiologic temperature and/or preserving a lungin a state that permits normal cellular metabolism, such as proteinsynthesis.

In certain embodiments solutions are formed from compositions bycombining components with a fluid, from more concentrated solutions bydilution, or from more dilute solutions by concentration. In exemplaryembodiments, suitable solutions include an energy source and one or moreamino acids selected and proportioned so that the organ continues itscellular metabolism during perfusion. Cellular metabolism includes, forexample conducting protein synthesis while functioning during perfusion.Some illustrative solutions are aqueous based, while other illustrativesolutions are non-aqueous, for example organic solvent-based,ionic-liquid-based, or fatty-acid-based.

The solutions may include one or more energy-rich components to assistthe organ in conducting its normal physiologic function. Thesecomponents may include energy rich materials that are metabolizable,and/or components of such materials that an organ can use to synthesizeenergy sources during perfusion. Exemplary sources of energy-richmolecules include, for example, one or more carbohydrates. Examples ofcarbohydrates include monosaccharides, disaccharides, oligosaccharides,polysaccharides, or combinations thereof, or precursors or metabolitesthereof. While not meant to be limiting, examples of monosaccharidessuitable for the solutions include octoses; heptoses; hexoses, such asfructose, allose, altrose, glucose, mannose, gulose, idose, galactose,and talose; pentoses such as ribose, arabinose, xylose, and lyxose;tetroses such as erythrose and threose; and trioses such asglyceraldehyde. While not meant to be limiting, examples ofdisaccharides suitable for the solutions include (+)-maltose(4-O-(□-D-glucopyranosyl)-□-D-glucopyranose), (+)-cellobiose(4-O-(□-D-glucopyranosyl)-D-glucopyranose), (+)-lactose(4-O-(□-D-galactopyranosyl)-□-D-glucopyranose), sucrose(2-O-(□-D-glucopyranosyl)-□-D-fructofuranoside). While not meant to belimiting, examples of polysaccharides suitable for the solutions includecellulose, starch, amylose, amylopectin, sulfomucopolysaccharides (suchas dermatane sulfate, chondroitin sulfate, sulodexide, mesoglycans,heparan sulfates, idosanes, heparins and heparinoids), and glycogen. Insome embodiments, monossacharides, disaccharides, and polysaccharides ofboth aldoses, ketoses, or a combination thereof are used. One or moreisomers, including enantiomers, diastereomers, and/or tautomers ofmonossacharides, disaccharides, and/or polysaccharides, including thosedescribed and not described herein, may be employed in the solutionsdescribed herein. In some embodiments, one or more monossacharides,disaccharides, and/or polysaccharides may have been chemically modified,for example, by derivatization and/or protection (with protectinggroups) of one or more functional groups. In certain embodiments,carbohydrates, such as dextrose or other forms of glucose are preferred.

Other possible energy sources include adenosine triphosphate (ATP),co-enzyme A, pyruvate, flavin adenine dinucleotide (FAD), thiaminepyrophosphate chloride (co-carboxylase), β-nicotinamide adeninedinucleotide (NAD), (β-nicotinamide adenine dinucleotide phosphate(NADPH), and phosphate derivatives of nucleosides, i.e. nucleotides,including mono-, di-, and tri-phosphates (e.g., UTP, GTP, GDF, and UDP),coenzymes, or other bio-molecules having similar cellular metabolicfunctions, and/or metabolites or precursors thereof. For example,phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine),cytidine, and uridine, as well as other naturally and chemicallymodified nucleosides are contemplated.

In certain embodiments, one or more carbohydrates are provided alongwith a phosphate source, such as a nucleotide. One exemplarycarbohydrate is dextran. The carbohydrate helps enable the organ toproduce ATP or other energy sources during perfusion. The phosphatesource may be provided directly through ATP, ADP, AMP or other sources.In other illustrative embodiments, a phosphate is provided through aphosphate salt, such as glycerophosphate, sodium phosphate or otherphosphate ions. A phosphate may include any form thereof in any ionicstate, including protonated forms and forms with one or more counterions.

In some instances, additional components are provided to assist thelungs 1004 in conducting its metabolism during perfusion. Thesecomponents include, for example, forms or derivatives of adenine and/oradenosine, which may be used for ATP synthesis, for maintainingendothelial function, and/or for attenuating ischemia and/or reperfusioninjury. According to certain implementations, a magnesium ion source isprovided with a phosphate, and in certain embodiments, with adenosine tofurther enhance ATP synthesis within the cells of the perfused lungs1004.

Solutions described herein may include one or more amino acids,preferably a plurality of amino acids, to support protein synthesis bythe organ's cells. Suitable amino acids include, for example, any of thenaturally-occurring amino acids. The amino acids may be, in variousenantiomeric or diastereomeric forms. For example, solutions may employeither D- or L-amino acids, or a combination thereof, i.e. solutionsenantioenriched in more of the D- or L-isomer or racemic solutions.Suitable amino acids may also be non-naturally occurring or modifiedamino acids, such as citrulline, ornithine, homocystein, homoserine,β-amino acids such as β-alanine, amino-caproic acid, or combinationsthereof.

Certain exemplary solutions include some but not all naturally-occurringamino acids. In some embodiments, solutions include essential aminoacids. For example, a solution may be prepared with one or more or allof the following amino-acids:

Glycine Alanine Arginine Aspartic Acid Glutamic Acid HistidineIsoleucine Leucine Methionine Phenylalanine Proline Serine ThereonineTryptophan Tyrosine Valine Lysine acetate

In certain embodiments, non-essential and/or semi-essential amino acidsare not included in the solutions. For example, in some embodiments,asparagine, glutamine, and/or cysteine are not included. In otherembodiments, the solution contains one or more non-essential and/orsemi-essential amino acids. Accordingly, in other embodiments,asparagine, glutamine, and/or cysteine are included.

The solutions may also contain electrolytes, particularly calcium ionsfor facilitating enzymatic reactions, and/or coagulation within theorgan. Other electrolytes may be used, such as sodium, potassium,chloride, sulfate, magnesium and other inorganic and organic chargedspecies, or combinations thereof. It should be noted that any componentprovided hereunder may be provided, where valence and stability permit,in an ionic form, in a protonated or unprotonated form, in salt or freebase form, or as ionic or covalent substituents in combination withother components that hydrolyze and make the component available inaqueous solutions, as suitable and appropriate.

In certain embodiments, the solutions contain buffering components. Forexample, suitable buffer systems include 2-morpholinoethanesulfonic acidmonohydrate (MES), cacodylic acid, H₂CO₃/NaHCO₃ (pK_(a1)), citric acid(pK_(a3)), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane(Bis-Tris), N-carbamoylmethylimidino acetic acid (ADA),3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris Propane)(pK_(a1)), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES),N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), imidazole,N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES),3-(N-morpholino)propanesulphonic acid (MOPS), NaH₂PO₄/Na₂HPO₄ (pK_(a2)),N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES),N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acid (HEPES),N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid)(HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine(Tricine), tris hydroxymethylaminoethane (Tris), glycineamide,N,N-bis(2-hydroxyethyl) glycine (Bicine), glycylglycine (pK_(a2)),N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or acombination thereof. In some embodiments, the solutions contain sodiumbicarbonate, potassium phosphate, or TRIS buffer.

In another aspect, a blood product is provided with the solution tosupport the organ during metabolism. Exemplary suitable blood productsmay include whole blood, and/or one or more components thereof such asblood serum, plasma, albumin, and red blood cells. In embodiments wherewhole blood is used, the blood may be passed through a leukocyte andplatelet depleting filter to reduce pyrogens, antibodies and/or otheritems that may cause inflammation in the organ. Thus, in someembodiments, the solution employs whole blood that has been at leastpartially depleted of leukocytes and/or whole blood that has been atleast partially depleted of platelets.

The solutions are preferably provided at a physiologic temperature andmaintained thereabout throughout perfusion and recirculation. As usedherein, “physiologic temperature” is referred to as temperatures betweenabout 25° C. and about 37° C., for example, between about 30° C. andabout 37° C., such as between about 34° C. and about 37° C.

Table 1 sets forth components that are used in an exemplary aqueouspriming solution. The component amounts in Table 1 are relative to eachother and to the amount of aqueous solvent employed in the solution(about 500 mL in the exemplary embodiment) and may be scaled asappropriate. In certain embodiments, the quantity of aqueous solventvaries ±about 10%.

TABLE 1 Composition of Exemplary Priming Solution (about 500 mL aqueoussolution) Component Amount Specification Dextran  20 g ±about 50% SodiumChloride  4.8 g ±about 10% Potassium Chloride 185 mg ±about 10%Magnesium Sulfate heptahydrate 185 mg ±about 10% Sodium Glycerophosphate900 mg ±about 10%

With regard to the nutritional supplement solution 116, in certainembodiments it includes one or more carbohydrates and may also include aphosphate source. The nutritional supplement solution 116 is typicallymaintained at a pH of about 5.0 to about 6.5, for example about 5.5 toabout 6.0.

Table 2 sets forth components that are used in an exemplary nutritionalsupplement solution 116. In some embodiments, the nutritional solution116 further includes sodium glycerol phosphate. The amount of componentsin Table 2 is relative to the amount of aqueous solvent employed in thesolution 116 (about 500 mL) and may be scaled as appropriate. In someembodiments, the quantity of aqueous solvent varies ±about 10%.

TABLE 2 Components of Exemplary Nutritional Solution (about 500 mL)Component Amount Specification Dextrose 40 g ±about 10%

In certain embodiments the nutritional solution 116 includes one or morecarbohydrates and may also include a phosphate source. The nutritionalsolution 116 is typically maintained at a pH of about 5.0 to about 6.5,for example of about 5.5 to about 6.0.

Other components may be added to the preservation solution 118,including, for example, adenosine, magnesium, phosphate, calcium, and/orsources thereof. In some instances, additional components are providedto assist the organ in conducting its metabolism during perfusion. Thesecomponents include, for example, forms of adenosine, which may be usedfor ATP synthesis, for maintaining endothelial function, and/or forattenuating ischemia and/or reperfusion injury. Components may alsoinclude other nucleosides, such as guanosine, thymidine (5-Me-uridine),cytidine, and uridine, as well as other naturally and chemicallymodified nucleosides including nucleotides thereof. According to someimplementations, a magnesium ion source is provided with a phosphatesource, and in certain embodiments, with adenosine to further enhanceATP synthesis within the cells of the perfused organ. A plurality ofamino acids may also be added to support protein synthesis by theheart's 102 cells. Applicable amino acids may include, for example, anyof the naturally-occurring amino acids, as well as those mentionedabove.

Table 3 sets forth components that may be used in a solution 118 forpreserving an organ as described herein. The solution 118 may includeone or more of the components described in Table 3.

TABLE 3 Component of Exemplary Composition for Preservative SolutionExemplary Concentration Ranges in Preservative Component SolutionAlanine about 1 mg/L-about 10 g/L Arginine about 1 mg/L-about 10 g/LAsparagine about 1 mg/L-about 10 g/L Aspartic Acid about 1 mg/L-about 10g/L Cysteine about 1 mg/L-about 10 g/L Cystine about 1 mg/L-about 10 g/LGlutamic Acid about 1 mg/L-about 10 g/L Glutamine about 1 mg/L-about 10g/L Glycine about 1 mg/L-about 10 g/L Histidine about 1 mg/L-about 10g/L Hydroxyproline about 1 mg/L-about 10 g/L Isoleucine about 1mg/L-about 10 g/L Leucine about 1 mg/L-about 10 g/L Lysine about 1mg/L-about 10 g/L Methionine about 1 mg/L-about 10 g/L Phenylalanineabout 1 mg/L-about 10 g/L Proline about 1 mg/L-about 10 g/L Serine about1 mg/L-about 10 g/L Threonine about 1 mg/L-about 10 g/L Tryptophan about1 mg/L-about 10 g/L Tyrosine about 1 mg/L-about 10 g/L Valine about 1mg/L-about 10 g/L Adenine about 1 mg/L-about 10 g/L ATP about 10ug/L-about 100 g/L Adenylic Acid about 10 ug/L-about 100 g/L ADP about10 ug/L-about 100 g/L AMP about 10 ug/L-about 100 g/L Ascorbic Acidabout 1 ug/L-about 10 g/L D-Biotin about 1 ug/L-about 10 g/L VitaminD-12 about 1 ug/L-about 10 g/L Cholesterol about 1 ug/L-about 10 g/LDextrose (Glucose) about 1 g/L-about 150 g/L Multi-vitamin Adult about 1mg/L-about 20 mg/L or 1 unit vial Folic Acid about 1 ug/L-about 10 g/LGlutathione about 1 ug/L-about 10 g/L Guanine about 1 ug/L-about 10 g/LInositol about 1 g/L-about 100 g/L Riboflavin about 1 ug/L-about 10 g/LRibose about 1 ug/L-about 10 g/L Thiamine about 1 mg/L-about 10 g/LUracil about 1 mg/L-about 10 g/L Calcium Chloride about 1 mg/L-about 100g/L NaHCO₃ about 1 mg/L-about 100 g/L Magnesium sulfate about 1mg/L-about 100 g/L Potassium chloride about 1 mg/L-about 100 g/L Sodiumglycerophosphate about 1 mg/L-about 100 g/L Sodium Chloride about 1mg/L-about 100 g/L Sodium Phosphate about 1 mg/L-about 100 g/L Insulinabout 1 IU-about 150 IU Serum albumin about 1 g/L-about 100 g/L Pyruvateabout 1 mg/L-about 100 g/L Coenzyme A about 1 ug/L-about 10 g/L Serumabout 1 ml/L-about 100 ml/L Heparin about 500 U/L-about 1500 U/LSolumedrol about 200 mg/L-about 500 mg/L Dexamethasone about 1mg/L-about 1 g/L FAD about 1 ug/L-about 10 g/L NADP about 1 ug/L-about10 g/L adenosine about 1 mg/L-about 10 g/L guanosine about 1 mg/L-about10 g/L GTP about 10 ug/L-about 100 g/L GDP about 10 ug/L-about 100 g/LGMP about 10 ug/L-about 100 g/L

Table 4 sets forth components that are used in an exemplary preservativesolution 118. The amounts provided in Table 4 describe preferred amountsrelative to other components in the table and may be scaled to providecompositions of sufficient quantity. In some embodiments, the amountslisted in Table 4 can vary by ±about 10% and still be used in thesolutions described herein.

TABLE 4 Components of Exemplary Preservative Solution Component AmountAdenosine About 675 mg-About 825 mg Calcium Chloride dihydrate About2100 mg-About 2600 mg Glycine About 315 mg-About 385 mg L-Alanine About150 mg-About 200 mg L-Arginine About 600 mg-About 800 mg L-Aspartic AcidAbout 220 mg-About 270 mg L-Glutamic Acid About 230 mg-About 290 mgL-Histidine About 200 mg-About 250 mg L-Isoleucine About 100 mg about130 mg L-Leucine About 300 mg-About 380 mg L-Methionine About 50mg-About 65 mg L-Phenylalanine About 45 mg-About 60 mg L-Proline About110 mg-About 140 mg L-Serine About 80 mg-About 105 mg L-Thereonine About60 mg-About 80 mg L-Tryptophan About 30 mg-About 40 mg L-Tyrosine About80 mg-About 110 mg L-Valine About 150 mg-About 190 mg Lysine AcetateAbout 200 mg-About 250 mg Magnesium Sulfate Heptahydrate About 350mg-About 450 mg Potassium Chloride About 15 mg-About 25 mg SodiumChloride About 1500 mg-About 2000 mg Dextrose About 25 gm-About 120 gmInsulin About 75 Units-About 150 Units MVI-Adult 1 unit vial SoluMedrolabout 200 mg-500 mg Sodium Bicarbonate About 10-25 mEq

In the exemplary embodiment of a solution 118, the components in Table 4are combined in the relative amounts listed therein per about 1 L ofaqueous fluid to form the solution 118. In some embodiments, thecomponents in Table 4 are combined in the relative amounts listedtherein per about 500 mL of aqueous fluid and then combined with thesolution 116, also about 500 mL, to provide a maintenance solution116/118 of about 1 L of aqueous fluid. In some embodiments the quantityof aqueous fluid in solutions 116, 118, and/or 116/118 can vary ±about10%. The pH of the solution 118 may be adjusted to be between about 7.0and about 8.0, for example about 7.3 and about 7.6. The solution 118 maybe sterilized, for example by autoclaving, to provide for improvedpurity.

Table 5 sets forth another exemplary preservative solution 118,comprising a tissue culture media having the components identified inTable 5 and combined with an aqueous fluid, which may be used in theperfusion fluid 108 as described herein. The amounts of componentslisted in Table 5 are relative to each other and to the quantity ofaqueous solution used. In some embodiments, about 500 mL of aqueousfluid is used. In other embodiments about 1 L of aqueous fluid is used.For example, combination of about 500 mL of preservative solution 118with 500 mL of nutritional solution 116 affords a maintenance solution116/118 of about 1 L. In some embodiments, the quantity of aqueoussolution can vary ±about 10%. The component amounts and the quantity ofaqueous solution may be scaled as appropriate for use. The pH of thepreservative solution 118, in this embodiment, may be adjusted to beabout 7.0 to about 8.0, for example about 7.3 to about 7.6.

TABLE 5 Composition of Another Exemplary Preservative Solution (about500 mL aqueous solution) Tissue Culture Component Amount SpecificationAdenosine 750 mg ±about 10% Calcium Chloride dihydrate 2400 mg  ±about10% Glycine 350 mg ±about 10% L-Alanine 174 mg ±about 10% L-Arginine 700mg ±about 10% L-Aspartic Acid 245 mg ±about 10% L-Glutamic Acid 258 mg±about 10% L-Histidine 225 mg ±about 10% L-Isoleucine 115.5 mg   ±about10% L-Leucine 343 mg ±about 10% L-Methionine  59 mg ±about 10%L-Phenylalanine  52 mg ±about 10% L-Proline 126 mg ±about 10% L-Serine 93 mg ±about 10% L-Thereonine  70 mg ±about 10% L-Tryptophan  35 mg±about 10% L-Tyrosine  92 mg ±about 10% L-Valine 171.5 mg   ±about 10%Lysine Acetate 225 mg ±about 10% Magnesium Sulfate 400 mg ±about 10%Heptahydrate Potassium Chloride  20 mg ±about 10% Sodium Chloride 1750mg  ±about 10%

Since amino acids are the building blocks of proteins, the uniquecharacteristics of each amino acid impart certain important propertieson a protein such as the ability to provide structure and to catalyzebiochemical reactions. The selection and concentrations of the aminoacids provided in the preservative solutions provide support of normalphysiologic functions such as metabolism of sugars to provide energy,regulation of protein metabolism, transport of minerals, synthesis ofnucleic acids (DNA and RNA), regulation of blood sugar and support ofelectrical activity, in addition to providing protein structure.Additionally, the concentrations of specific amino acids found in thepreservative solutions can be used to predictably stabilize the pH ofthe maintenance solution 116/118 and perfusion fluid 108.

In one embodiment, a maintenance solution 116/118 is made from acombination of the preservative solution 118, including one or moreamino acids, and the nutritional solution 116, including one or morecarbohydrates, such as glucose or dextrose. The maintenance solution116/118 may also have additives, such as those described herein,administered at the point of use just prior to infusion into the organperfusion system. For example, additional additives that can be includedwith the solution or added at the point of use by the user includehormones and steroids, such as dexamethasone and insulin, prostacyclineand other members of the prostoglandine family, beta-1-agonists (e.g.,albuterol, isopreternaol), vitamins, such as an adult multi-vitamin, forexample adult multivitamins for infusion, such as MVI-Adult. Additionalsmall molecules and large bio-molecules may also be included with thesolution or added at the point of use by the user at port 762, forexample, therapeutics and/or components typically associated with bloodor blood plasma, such as albumin.

The solutions may include therapeutic components to help maintain thelungs 1004 and protect them against ischemia, reperfusion injury andother ill effects during perfusion, to help mitigate edema, or providegeneral endothelial tissue support for the lungs 1004. In certainexemplary embodiments these components may include hormones (e.g.,insulin), vitamins (e.g., an adult multi-vitamin, such as multi-vitaminMVI-Adult), and/or steroids (e.g., dexamethasone and SoluMedrol). Insome embodiments, therapeutics that are included in the compositions andsolutions for organ maintenance to help mitigate edema, provideendothelial support, and otherwise provide preventative or prophylactictreatment to the lungs 1004. In certain embodiments, the systemsdescribed herein include hormones, such as thyroid hormones, for exampleT₃ and/or T₄ thyroid hormones added to the nutritional solution 116, thepreservative solution 118, and/or the maintenance solutions 116/118either before or during perfusion of the organ. Additional exemplarytherapeutics include isuprel, flolan, prostacyclin or otherprostaglandin, beta-1-agonists, beta-2-antagonists, brochodilators,isoproterenol, pentoxifylline, and nitric oxide donors (e.g.,L-arginine, nitroglycerine, nitroprusside). The above therapeutics mayalso be added directly to the system, for example, to the perfusionfluid 108, before or during perfusion of the organ. In certainembodiments, colloids are added, such as dextran, albumin, hydroxyethylstarches, or gelatins. Other components that may be added includeanti-microbial agents, anti-fungal agents, anti-viral agents,vasodilators, surfactants adapted to resist collapsing of alveoli withinthe lung. and anti-inflammatory drugs.

In particular, the addition of dextran offers numerous benefitsincluding improving erythrocyte deformability, preventing erythrocyteaggregation, inducing disbanding of already aggregated cells, improvingpulmonary circulation and preserving endothelial-epithelial membrane.Dextran also has anti-thrombotic effects by being able to coatendothelial surfaces and platelets. The addition of prostaglandins intovarious solutions induce effects such as vasodilation of pulmonaryvascular bed, inhibition of platelet aggregation, bronchilation,reducing endothelia permeability and reducing neutrophil adhesion. Inaddition, nitric oxide is used to treat ischemia-reperfusion injury ofthe lungs 1004 because it can improve ventilation-perfusion mismatch anddecrease pulmonary artery pressures. Isoproterenol, as a therapeuticagent, acts a non-selective beta-adrenergic agonist. It is adapted torelax almost all varieties of smooth muscles, hence preventing orrelieving broncho-constriction and producing pulmonary vasodilation.Moreover, therapeutics such as surfactants prevent the collapsing ofalveoli within the lungs 1004 during the breathing cycle as well asprotect the lungs 1004 from injuries and infections caused by foreignbodies and pathogens. Pentoxifylline, as a therapeutic agent,ameliorates ischemia-reperfusion injury by, for example, inhibitingleukocyte sequestration in the lungs 1004, thus preventing the releaseof free radicals and cytokin.

The one or more therapeutics or other additives may be delivered to thelung through the tracheal interface 1024 via a nebulizer, or added tothe perfusion fluid 108 through the maintenance solution, or added byinjection directly into the perfusion fluid reservoir at the point ofuse. In certain embodiments, therapeutic agents such as nitric oxide areprovided indirectly to the explanted lungs 1004 through theadministration of an upstream precursor molecule such as L-arginine orthrough the infusion of a nitric oxide donor such as nitroglycerin ornitroprusside. In certain embodiments, therapeutics such asbronchodilators are provided to the lungs 1004 in an injectable forminto the perfusion fluid 108 or through the tracheal interface 1024 in anebulized form. In certain embodiments, exogenous surfactants aredelivered to the lungs 1004 through the tracheal interface 1024 orprovided to different sections of the lungs 1004 using bronchoscopy. Incertain embodiments, pentoxifylline is added to the perfusion fluid 108in an injectable form.

With further reference to Table 4, certain components used in theexemplary preservation solution 118 are molecules, such as small organicmolecules or large bio-molecules, that would be inactivated, for examplethrough decomposition or denaturing, if passed through sterilization.According to the system 100, the inactivatable components of thesolution 118 may be prepared separately from the remaining components ofthe solution 118. The separate preparation involves separately purifyingeach component through known techniques. The remaining components of thesolution 118 are sterilized, for example through an autoclave, thencombined with the biological components.

Table 6 lists certain biological components that may be separatelypurified and added to the solutions described herein aftersterilization, according to this two-step process. These additional orsupplemental components may be added to solutions 118, 116, 116/118, thepriming solution or a combination thereof individually, in variouscombinations, all at once as a composition, or as a combined solution.For example, in certain embodiments, the epinephrine, insulin, andMVI-Adult, listed in Table 6, are added to the maintenance solution116/118. In another example, the SoluMedrol and the sodium bicarbonate,listed in Table 6, are added to the priming solution. The additionalcomponents may also be combined in one or more combinations or alltogether and placed in solution before being added to solutions 116,118, 116/118, and/or the priming solution. In some embodiments, theadditional components are added directly to the perfusion fluid 108through port 762. The component amounts listed in Table 6 are relativeto each other and/or to the amounts of components listed in one or moreof Tables 1-5 as well as the amount of aqueous solution used inpreparing solutions 116, 118, 116/118, and/or the priming solution andmay be scaled as appropriate for the amount of solution required.

TABLE 6 Exemplary Biological Components Added Prior to Use ComponentAmount Type Specification Insulin about 100 Units Hormone ±about 10%MVI-Adult 1 mL unit vial Vitamin ±about 10% SoluMedrol About 250 mgSteroid ±about 10% Sodium About 20 mEq Buffer ±about 10% Bicarbonate

In one embodiment, a composition for use in a maintenance solution116/118 is provided comprising one or more carbohydrates, one or moreorgan stimulants, and a plurality of amino acids that do not includeasparagine, glutamine, or cysteine. The composition may also includeother substances, such as those used in solutions described herein.

In another embodiment, a system for perfusing an organ, such as a heart,is provided comprising an organ and a substantially cell-freecomposition, comprising one or more carbohydrates, one or more organstimulants, and a plurality of amino acids that do not includeasparagine, glutamine, or cysteine. Substantially cell-free includessystems that are substantially free from cellular matter; in particular,systems that are not derived from cells. For example, substantiallycell-free includes compositions and solutions prepared from non-cellularsources.

In another aspect, the solutions 116 and 118 may be provided in the formof a kit that includes one or more organ maintenance solutions. Anexemplary maintenance solution may include components identified abovein one or more fluid solutions for use in an organ perfusion fluid 108.In certain embodiments, the maintenance solution 116/118 may includemultiple solutions, such as a preservation solution 118 and anutritional solution 116 and/or a supplemental composition or solution,or may include dry components that may be regenerated in a fluid to formone or more solutions 116/118. The kit may also comprise components fromthe solutions 116 and/or 118 in one or more concentrated solutionswhich, on dilution, provide a preservation, nutritional, and/orsupplemental solution as described herein. The kit may also include apriming solution. In an exemplary embodiment, the maintenance solutionincludes a preservation solution 118 and a nutritional solution 116 suchas those described above, and a priming solution such as that describedabove.

In certain embodiments, the kit is provided in a single package, whereinthe kit includes one or more solutions (or components necessary toformulate the one or more solutions by mixing with an appropriatefluid), and instructions for sterilization, flow and temperature controlduring perfusion and use and other information necessary or appropriateto apply the kit to organ perfusion. In certain embodiments, a kit isprovided with only a single solution 116, 118 and/or 116/118 (or set ofdry components for use in a solution upon mixing with an appropriatefluid), and the single solution 116, 118 and/or 116/118 (or set of drycomponents) is provided along with a set of instructions and otherinformation or materials necessary or useful to operate the solution116, 118 and/or 116/118 in the system 100.

In another aspect, the systems, solutions and methods may be used todeliver therapeutics to an organ during perfusion. For example, one ormore of the solutions and/or systems described above may include one ormore drugs, biologics, gene therapy vectors, or other therapeutics whichare delivered to the organ during perfusion. Suitable exemplarytherapeutics may include drugs, biologics, or both. Suitable drugs mayinclude, for example, anti fungals, anti-microbials or anti-biotics,anti-inflamatories, anti-proliferatives, anti-virals, steroids,retinoids, NSAIDs, vitamin D3 and vitamin D3 analogs, calcium channelblockers, complement neutralizers, ACE inhibitors, immuno-suppressants,and other drugs. Suitable biologics may include proteins; suitablebiologics may also include vectors loaded with one or more genes forgene therapy application.

For example, suitable steroids include but are not limited to androgenicand estrogenic steroid hormones, androgen receptor antagonists and5-α-reductase inhibitors, and corticosteroids. Specific examples includebut are not limited to alclometasone, clobetasol, fluocinolone,fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone,prednisone, prednisolone, methylprednisolone, triamcinolone,betamethasone, and dexamethasone, and various esters and acetonidesthereof.

Suitable retinoids include but are not limited to retinol, retinal,isotretinoin, acitretin, adapalene, tazarotene, and bexarotene.

Suitable NSAIDs include but are not limited to naproxen, suprofen,ketoprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin,celecoxib, and rofecoxib.

Suitable vitamin D3 analogues include but are not limited todoxercalciferol, seocalcitol, calcipotriene, tacalcitol, calcitriol,ergocalciferol, and calcifediol.

Suitable anti-viral agents include but are not limited to trifluridine,cidofovir, acyclovir, penciclovir, famciclovir, valcyclovir,gancyclovir, and docosanol.

Suitable human carbonic anhydrase inhibitors include but are not limitedto methazoliamide, acetazolamide, and dorzolamide.

Suitable anti-proliferative agents include but are not limited to 5-FU,taxol, daunorubicin, and mitomycin.

Suitable antibiotic (antimicrobial) agents include but are not limitedto bacitracin, chlorhexidine, chlorhexidine digluconate, ciprofloxacin,clindamycin, erythromycin, gentamicin, lomefloxacin, metronidazole,minocycline, moxifloxacin, mupirocin, neomycin, ofloxacin, polymyxin B,rifampicin, ruflozacin, tetracycline, tobramycin, triclosan, andvancomycin. The antiviral and antibacterial prodrugs described hereinmay be used to treat appropriately responsive systemic infections.

In certain embodiments, a solution system for use in a perfusion fluid108, comprising a first chamber containing a first solution, such as apreservation solution 118, that includes one or more cardio stimulantsand a plurality of amino acids that do not include asparagine,glutamine, or cysteine, and a second chamber, containing a secondsolution, such as a nutritional solution 116, that includes one or morecarbohydrates, such as dextrose. The system may also include asterilization system for sterilizing the first solution and the secondsolution prior to using the solutions to perfuse a heart. In someembodiments, one or more of the solutions 118 and 116 includes one ormore therapeutics. In some embodiments the solution system includes athird chamber comprising a priming solution, such as is described above,which may have one or more carbohydrates. In certain embodiments, thefirst solution 118 includes adenosine, insulin, one or moreimmuno-suppressants, a multi-vitamin, and/or one or more electrolytes.

It is to be understood that while the invention has been described inconjunction with the various illustrative embodiments, the forgoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Forexample, a variety of systems and/or methods may be implemented based onthe disclosure and still fall within the scope of the invention. Otheraspects, advantages, and modifications are within the scope of thefollowing claims. All references cited herein are incorporated byreference in their entirety and made part of this application.

1. A method for perfusing a lung ex vivo, comprising: connecting thelung within a fluid perfusion circuit, flowing a perfusion fluid intothe lung through a pulmonary artery interface and away from the lungthrough a pulmonary vein interface, providing a respiratory gas to thelung for use in metabolism by the lung, the respiratory gas having apre-determined composition of oxygen, and ventilating the lung through atracheal interface, wherein the perfusion fluid flowing into the lungincludes a first gas component at a substantially constant firstcomposition, and the perfusion fluid flowing away from the lung includesthe first gas component at a substantially constant second composition.2. The method of claim 1, wherein ventilating occurs by flowing therespiratory gas through the tracheal interface.
 3. The method of claim2, comprising removing carbon dioxide produced by the lung through thetracheal interface.
 4. The method of claim 2, wherein the firstcomposition of the first gas component is substantially equivalent tothe second composition of the first gas component.
 5. The method ofclaim 2, wherein oxygen is maintained in the perfusion fluid flowinginto the lung at a partial pressure substantially equivalent to thepartial pressure of oxygen in the perfusion fluid flowing out of thelung.
 6. The method of claim 2, wherein carbon dioxide is maintained inthe perfusion fluid flowing into the lung at a partial pressure that issubstantially equivalent to the partial pressure of carbon dioxide inthe perfusion fluid flowing out of the lung.
 7. The method of claim 2,wherein the respiratory gas flowing through the tracheal interfaceincludes a composition of oxygen, carbon dioxide, and an inertrespiratory gas.
 8. The method of claim 7, wherein the inert respiratorygas is one of nitrogen and helium.
 9. The method of claim 7, wherein therespiratory gas flowing through the tracheal interface includes at leastabout 10% to about 20% oxygen and at least about 2% to about 8% carbondioxide.
 10. The method of claim 9, wherein the respiratory gas is about14% oxygen and about 5% carbon dioxide.
 11. The method of claim 1comprising oxygenating the perfusion fluid to a desired level prior toinitiating perfusion of the lung.
 12. The method of claim 1, comprisingdelivering the respiratory gas from a first gas source to the perfusionfluid through a gas exchange device connected within the perfusioncircuit.
 13. The method of claim 12, comprising removing carbon dioxideproduced by the lung through the gas exchange device.
 14. The method ofclaim 12, wherein ventilating the lung comprises delivering an isolatedgas volume through the tracheal interface.
 15. The method of claim 14,wherein the isolated volume gas source is provided by a flexible bag.16. The method of claim 14, wherein the isolated volume gas source isprovided by a hose.
 17. The method of claim 14, wherein the isolatedvolume gas source includes gas components that reach a substantiallyconstant composition within the isolated volume by exchanging with gascomponents in the perfusion fluid.
 18. The method of claim 12, whereinthe first composition of the first gas component differs from the secondcomposition of the first gas component by an amount substantiallyequivalent to a quantity of the first gas component metabolized by thelung.
 19. The method of claim 12, wherein the first gas source includesa composition of oxygen, carbon dioxide, and an inert respiratory gas.20. The method of claim 19, wherein the inert respiratory gas is one ofnitrogen and helium.
 21. The method of claim 19, wherein the first gassource includes a composition of about 11% to about 14% oxygen and about3% to about 7% carbon dioxide.
 22. The method of claim 20, wherein thefirst gas source includes a composition of about 12% oxygen and about 5%carbon dioxide.
 23. The method of claim 12, comprising oxygenating theperfusion fluid with a second gas source through the gas exchangedevice.
 24. The method of claim 12, wherein oxygen is maintained duringperfusion at an equilibrium partial pressure that is greater in theperfusion fluid flowing into the lung than in the perfusion fluidflowing out of the lung.
 25. The method of claim 12, wherein carbondioxide is maintained during perfusion at an equilibrium partialpressure that is lower in the perfusion fluid flowing into the lung thanin the perfusion fluid flowing out of the lung.
 26. The method of claim1, wherein the first composition of the first gas component is a partialpressure that is greater than a partial pressure of the first gascomponent in a predetermined first level, and less than a composition ofthe first gas component in a predetermined second level.
 27. The methodof claim 26, wherein the predetermined first level is the partialpressure of the first gas component in physiologic venous blood, and thepredetermined second level is the partial pressure of the first gascomponent in physiologic arterial blood.
 28. The method of claim 26,wherein the first gas component is oxygen.
 29. The method of claim 27,wherein oxygen in the perfusion fluid flowing into the lung ismaintained during perfusion at a partial pressure of about 75 mmHg toabout 100 mmHg.
 30. The method of claim 27, wherein oxygen in theperfusion fluid flowing into the lung is maintained during perfusion ata partial pressure of about 80 mmHg to about 90 mmHg.
 31. The method ofclaim 30, wherein oxygen in the perfusion fluid flowing into the lung ismaintained during perfusion at a partial pressure of about 83 mmHg toabout 85 mmHg.
 32. The method of claim 1, wherein the first compositionof the first gas component is a partial pressure that is less than apartial pressure of the first gas component in a predetermined firstlevel, and greater than a composition of the first gas component in apredetermined second level.
 33. The method of claim 32, wherein thepredetermined first level is the partial pressure of the first gascomponent in physiologic venous blood, and the predetermined secondlevel is the partial pressure of the first gas component in physiologicarterial blood.
 34. The method of claim 33, wherein the first gascomponent is carbon dioxide.
 35. The method of claim 33, wherein carbondioxide in the perfusion fluid flowing into the lung is maintainedduring perfusion at a partial pressure of about 40 mmHg to about 50mmHg.
 36. The method of claim 33, wherein carbon dioxide in theperfusion fluid flowing into the lung is maintained during perfusion ata partial pressure of about 42 mmHg to about 48 mmHg.
 37. The method ofclaim 1 comprising maintaining the perfusion fluid provided to the lungat a near physiologic temperature.
 38. The method of claim 1 comprisingmeasuring a level of an arterial-venous (AV) oxygen gradient between theperfusion fluid flowing into the lung and flowing out of the lung. 39.The method of claim 1 comprising measuring at least one of a level ofoxygen saturation of blood hemoglobin and a partial pressure of oxygenin the perfusion fluid flowing into the lung.
 40. The method of claim 1comprising measuring at least one of a level of oxygen saturation ofblood hemoglobin and a partial pressure of oxygen in the perfusion fluidflowing out of the lung.
 41. The method of claim 1, wherein theperfusion fluid includes whole blood.
 42. The method of claim 1,comprising delivering one or more therapeutics to the lung duringperfusion.
 43. The method of claim 42, wherein the one or moretherapeutics are selected from antimicrobials, vasodilators, andanti-inflammatory drugs.
 44. The method of claim 42, wherein the one ormore therapeutics are selected from isuprel, flolan, prostacycline,dextran, prostaglandins, isoproterenol, bronchodilators, surfactants,pentoxifylline and nitric oxide donors.
 45. The method of claim 42,wherein the one or more therapeutics are delivered through the trachealinterface through one of a nebulizer and a bronchoscope.
 46. The methodof claim 1, comprising at least partially depleting the perfusion fluidof leukocytes.
 47. The method of claim 1, comprising at least partiallydepleting the perfusion fluid of platelets.
 48. The method of claim 1,comprising ventilating the lung by flowing gas through the trachealinterface. 49-76. (canceled)
 77. A method for evaluating a lung fortransplant suitability comprising: positioning the lung in an ex vivoperfusion circuit, flowing a perfusion fluid into the lung through apulmonary artery interface and flowing the perfusion fluid away from thelung through a pulmonary vein interface, the perfusion fluid being at aphysiologic temperature, providing a gas to the lung through a trachealinterface, measuring a first composition of a gas component in theperfusion fluid, and performing an evaluation on the lung based on thefirst composition.
 78. The method of claim 77, wherein the perfusionfluid has a physiologic venous composition.
 79. The method of claim 77,wherein the flow of the gas through the tracheal interface comprisesabout 100% oxygen.
 80. The method of claim 77, wherein the flow of thegas through the tracheal interface comprises ambient air.
 81. The methodof claim 77, wherein the evaluation includes measuring a fractionalinspired oxygen concentration.
 82. The method of claim 77, wherein theevaluation includes measuring an arterial-venous (AV) oxygen gradientbetween the perfusion fluid flowing into the lung and the perfusionfluid flowing away from the lung.
 83. The method of claim 77, whereinthe evaluation includes measuring an alveolar arterial (AA) oxygengradient.
 84. The method of claim 77, wherein the evaluation includesmeasuring a tidal volume.
 85. The method of claim 77, wherein theevaluation includes measuring at least one of a level of oxygensaturation of blood hemoglobin and a partial pressure of oxygen in theperfusion fluid flowing into the lung.
 86. The method of claim 77,wherein the evaluation includes measuring at least one of a level ofoxygen saturation of blood hemoglobin and a partial pressure of oxygenin the perfusion fluid flowing away from the lung.
 87. The method ofclaim 77, wherein the evaluation includes measuring a positive endexpiratory pressure.
 88. The method of claim 77, comprising measuring asaturation of oxygen in the perfusion fluid flowing through thepulmonary artery interface at a plurality of times during a period oftesting, measuring a saturation of oxygen in the perfusion fluid flowingthrough the pulmonary vein interface at the plurality of times duringthe period of testing, comparing pulmonary artery and pulmonary veinoxygen saturation measurements at each of the plurality of times todetermine comparative differences at the plurality of times, andidentifying a maximum difference among the comparative differences. 89.The method of claim 88, wherein the flow of the gas through the trachealinterface comprises about 100% oxygen.
 90. The method of claim 88,wherein the flow of the gas through the tracheal interface is less than100% oxygen.
 91. The method of claim 88, wherein the flow of the gasthrough the tracheal interface is less than 75% oxygen.
 92. The methodof claim 91, wherein the flow of the gas through the tracheal interfaceis less than 50% oxygen.
 93. The method of claim 92, wherein the flow ofthe gas through the tracheal interface is less than 25% oxygen.
 94. Themethod of claim 93, wherein the flow of the gas through the trachealinterface contains no oxygen.
 95. The method of claim 77, comprisingapplying a suction force through the tracheal interface to clear lungalveoli of debris.
 96. The method of claim 77, comprising causing thelung to inhale breaths that are of variable volume to clear lung alveoliof debris.
 97. The method of claim 96, wherein the breaths include afirst breath having a volume that is larger than the volume of at leasttwo next breaths.
 98. The method of claim 77, comprising adjusting acomposition of the flow of gas to the lung after measuring the firstcomposition of the gas component, measuring a second composition of thegas component in the perfusion fluid after adjusting the composition ofthe flow of gas; comparing the measurements of the first and secondcompositions of the gas component; and performing the evaluation basedon the comparison.
 99. A composition for use in a solution for perfusinga lung, comprising one or more carbohydrates that include dextran, and aplurality of amino acids that do not include asparagine, glutamine, orcysteine.
 100. The composition of claim 99, further comprising a bloodproduct.
 101. The composition of claim 99, further comprising wholeblood.
 102. The composition of claim 101, further comprising whole bloodthat has been at least partially depleted of leukocytes.
 103. Thecomposition of claim 101, further comprising whole blood that has beenat least partially depleted of platelets.
 104. The composition of claim99, further comprising a phosphate.
 105. The composition of claim 99,further comprising insulin.
 106. The composition of claim 99, furthercomprising at least one vitamin.
 107. The composition of claim 99,further comprising a magnesium ion source.
 108. The composition of claim99, further comprising one or more electrolytes.
 109. The composition ofclaim 108, wherein the one or more electrolytes includes potassium,sodium, calcium, chloride, sulfate, or a combination thereof.
 110. Thecomposition of claim 99, further comprising an immunosuppressant. 111.The composition of claim 110, further comprising a steroid.
 112. Thecomposition of claim 111, further comprising a colloid.
 113. Thecomposition of claim 112, wherein the colloid is selected from dextran,albumen, hyperstarch, and gelatin.
 114. The composition of claim 113,comprising dextran.
 115. The composition of claim 99, further comprisingone or more therapeutic.
 116. The composition of claim 112 wherein theone or more therapeutic is selected from antimicrobial, antifungal,antiviral, vasodilators, surfactants adapted to resist collapsing ofalveoli within the lung, and anti-inflammatory drugs.
 117. Thecomposition of claim 112, wherein the one or more therapeutic is avasodilator.
 118. The composition of claim 117, wherein the vasodilatoris selected from beta-1-agonist, isoproterenol and prostaglandine. 119.The composition of claim 112, wherein the one or more therapeutic isselected from pentoxifylline, isuprel, flolan, prostacycline and anitric oxide donor.
 120. The composition of claim 119, furthercomprising a nitric oxide donor selected from L-arginine,nitroglycerine, and nitroprusside.
 121. The composition of claim 112,wherein the one or more therapeutic is formulated for delivery throughthe tracheal interface by one of a nebulizer and a bronchoscope. 122.The composition of claim 121, wherein the one or more therapeutic isselected from prostaglandines and brochodilators.
 123. The compositionof claim 122, wherein the one or more therapeutic is beta-2 agonist.124. The composition of claim 99, further comprising a vector loadedwith one or more genes.
 125. The composition of claim 99, furthercomprising an aqueous medium.
 126. The composition of claim 99,comprising: Calcium Chloride dihydrate Glycine Alanine Arginine AsparticAcid Glutamic Acid Histidine Isoleucine Leucine Methionine PhenylalanineProline Serine Thereonine Fryptophan Tyrosine Valine L-Arginine LysineMagnesium Sulfate Heptahydrate Potassium Chloride Sodium ChlorideDextrose Sodium Glycerophosphate Insulin MVI-Adult SoluMedrol SodiumBicarbonate


127. The composition of claim 126, comprising the following componentsin the following amounts per about 1000 mL of aqueous medium: ComponentAmount Calcium Chloride dihydrate about 2100 mg-about 2600 mg Glycineabout 315 mg-about 385 mg L-Alanine about 150 mg-about 200 mg L-Arginineabout 600 mg-about 800 mg L-Aspartic Acid about 220 mg-about 270 mgL-Glutamic Acid about 230 mg-about 290 mg L-Histidine about 200 mg-about250 mg L-Isoleucine about 100 mg about 130 mg L-Leucine about 300mg-about 380 mg L-Methionine about 50 mg-about 65 mg L-Phenylalanineabout 45 mg-about 60 mg L-Proline about HOmg-about 140 mg L-Serine about80 mg-about 105 mg L-Thereonine about 60 mg-about 80 mg L-Tryptophanabout 30 mg-about 40 mg L-Tyrosine about 80 mg-about HOmg L-Valine about150 mg-about 190 mg Lysine Acetate about 200 mg-about 250 mg MagnesiumSulfate Heptahydrate about 350 mg-about 450 mg Potassium Chloride about15 mg-about 25 mg


128. The composition of claim 127, further including a priming solutioncomprising the following components in the following relative amounts:Component Amount Sodium Chloride about 4.8 g Potassium Chloride about185 mg{circumflex over ( )} Magnesium Sulfate heptahydrate about 185 mgSodium Glycerophosphate about 900 mg


129. The composition of claim 128, wherein the priming solution furtherincludes about 10 g to about 30 g of dextran.
 130. The composition ofclaim 128, wherein the priming solution further includes aqueous fluid.131. The composition of claim 130, wherein the components of the primingsolution are in relative amounts per about 500 mL of aqueous fluid. 132.The composition of claim 99, wherein the composition, when perfused withwhole blood through a lung, prolongs the lung's ability to continueperforming physiologic oxygen and carbon dioxide gas exchange ex vivo ata physiologic temperature.